QRD Human Product Information Annotated Template (EN) v.9 - clean
An Analysis and Evaluation of the Development of …...An Analysis and Evaluation of the Development...
Transcript of An Analysis and Evaluation of the Development of …...An Analysis and Evaluation of the Development...
An Analysis and Evaluation of the Development of the
QRD Human Product Information Template used in
Package Leaflets
Dissertation
to obtain the doctoral degree (Dr. rer. nat.)
from the Faculty of Mathematics and Natural Sciences at the
Rheinischen Friedrich-Wilhelms-University Bonn
submitted by
Anna Wolf
from Cambridge, Great Britain
Bonn 2015
Prepared with permission of the Faculty of Mathematics and Natural Sciences
at the Rheinischen Friedrich-Wilhelms-University Bonn
1st Examiner: Prof. Dr. Harald G. Schweim
2nd
Examiner: Prof. Dr. Ulrich Jaehde
Day of the doctoral examination: 23.02.2015
Year of publication: 2015
The work presented here was completed during the time period from June
2011 to August 2014 at the Pharmaceutical Institute of the Rheinischen
Friedrich-Wilhelms-University Bonn, Department of Drug Regulatory Affairs,
under the supervision of Professor Dr. Harald G. Schweim and Dr. Jörg Fuchs.
The following articles were published from the presented dissertation:
Wolf A, Fuchs J, Schweim HG. QRD Template Texts Intended for Package Inserts.
Pharm. Ind. 74, 1540-1549 (2012).
Wolf A, Fuchs J, Schweim HG. Readability of the European QRD Template - The
European QRD template version 8 in comparison to its predecessor and a shorter
model template. Pharm. Ind. 76, 1312-1322 (2014).
I
Contents list
List of abbreviations ................................................................................................................................... V
1. Introduction ........................................................................................................................................... 1
2. Objectives .............................................................................................................................................. 8
3. Materials and methods ........................................................................................................................... 9
3.1 Analysis of QRD template development up to the present day ..................................................... 9
3.2 The use of templates for the package leaflet in EU and non-EU countries.................................... 9
3.3 Analysis of QRD template implementation in package leaflets of centralised approved medicines
..................................................................................................................................................... 10
3.3 Readability test of the QRD template version 8, its predecessor and a model version ................ 15
3.3.1 Development of package leaflets in three different templates ..................................................... 15
3.3.2 Development of the questionnaire ............................................................................................... 16
3.3.3 Study execution ............................................................................................................................ 18
3.3.4 Statistical analysis ........................................................................................................................ 19
4. Results .......................................................................................................................................... 21
4.1 QRD template development up to the present day ....................................................................... 21
4.1.1 Number of QRD template words for package leaflets of OTC medicines ................................... 21
4.1.2 Repetitions, long sentences and abbreviations in the QRD template ........................................... 22
4.2 Development of the QRD template wording ............................................................................... 23
4.2.1 QRD template section headings ................................................................................................... 23
4.2.2 The information box .................................................................................................................... 24
4.2.3 Section 1 of the QRD template .................................................................................................... 28
4.2.4 Section 2 of the QRD template .................................................................................................... 29
4.2.5 Section 3 of the QRD template .................................................................................................... 31
4.2.6 Section 4 of the QRD template .................................................................................................... 32
4.2.7 Sections 5 and 6 of the QRD template ......................................................................................... 34
4.3 Templates and related legal requirements in selected European and non-European countries .... 35
4.3.1 United Kingdom: Historical development and documents influencing the content of the package
leaflet............................................................................................................................................ 36
4.3.3 Legal requirements and guidelines influencing the content of the package leaflet in Switzerland
..................................................................................................................................................... 41
4.3.5 Regulations and history of patient information and Consumer Medicine Information (CMI) in
New Zealand ................................................................................................................................ 46
4.3.6 Regulations and history of patient information and templates in the United States .................... 47
4.4 Comparison of QRD template version 9 to non-EU package leaflet templates ........................... 51
II
4.4.1 Comparison of QRD template version 9 to the Swiss package leaflet template .......................... 51
4.4.2 Comparison of QRD template 9 to the Australian core Consumer Medicine Information (CMI)
template ........................................................................................................................................ 57
4.4.3 Comparison of QRD template 9 to the New Zealand core Consumer Medicine Information
(CMI) template ............................................................................................................................. 61
4.4.4 Comparison of QRD template 9 to the different templates used in the Unites States for patient
information ................................................................................................................................... 63
4.4.4.1 Analysis of the content of the labelling for prescription medicines in the United States ............ 63
4.4.4.2 Information required in a medication guide (MedGuide) ............................................................ 64
4.4.4.3 Content of Consumer Medication Information (CMI) ................................................................. 64
4.4.4.4 Information intended for over-the-counter (OTC) medicines ...................................................... 64
4.5 Comparison of QRD template 9 to other templates published by non-EU countries .................. 67
4.6 Analysis of QRD template implementation in package leaflets of centralised approved medicines
..................................................................................................................................................... 72
4.6.1 Types of medicines registered using the centralised authorisation procedure at the EMA ......... 72
4.6.2 Use of the contents list and sentences contained in the information box at the start of the QRD
template for the package leaflet ................................................................................................... 75
4.6.3 Number of words caused by the QRD template, the list of local representatives of the marketing
authorisation holder, additional information for patients and health professionals ..................... 78
4.6.4 Reference in section 2 to section 6 for location of the list of other ingredients ........................... 81
4.6.5 Method of presenting the frequency of side effects ..................................................................... 81
4.6.6 Text headings and standard statements in section 2 of the package leaflet ................................. 84
4.6.7 Presentation of the list of local representatives of the marketing authorisation holder ............... 86
4.7 Readability test of the QRD template version 8, its predecessor and a model template .............. 88
4.7.1 Results of the pilot readability test ............................................................................................... 88
4.7.2 Description of the demographic data of involved participants .................................................... 89
4.7.3 Analysis of the time taken to answer, locatability and comprehensibility of 26 requested contents
..................................................................................................................................................... 92
4.7.4 Analysis of locatability and comprehensibility of QRD template texts intended at the start of the
package leaflet ............................................................................................................................. 95
4.7.5 Analysis of comprehensibility and ease of location of information in section 1 of the package
leaflet............................................................................................................................................ 96
4.7.6 Analysis of comprehensibility and ease of location of information in section 2 of the package
leaflet............................................................................................................................................ 97
4.7.7 Analysis of comprehensibility and ease of location information in section 3 of the package
leaflet.......................................................................................................................................... 108
III
4.7.8 Analysis of comprehensibility and ease of location of information in section 4 of the package
leaflet.......................................................................................................................................... 112
4.7.9 Analysis of comprehensibility and ease of location of information in section 5 of the package
leaflet.......................................................................................................................................... 119
4.7.10 Analysis of comprehensibility and ease of location of information in section 6 of the package
leaflet.......................................................................................................................................... 120
4.8 Participants’ opinions on the package leaflet printed in the three templates ............................. 122
4.8.1 Opinions on the structure of the package leaflet ........................................................................ 122
4.8.2 Opinions on the comprehensibility of the package leaflet ......................................................... 124
4.8.3 Opinions on the information contained in the package leaflets ................................................. 126
4.8.4 Opinions on the readability and motivation to read the package leaflet .................................... 128
4.8.5 Opinions on confidence in the package leaflet and the medicine .............................................. 129
4.9 Participants’ additional opinions on the package leaflet and suggestions for what should be
included or deleted ..................................................................................................................... 131
4.10 Dependence of the readability test results on demographic factors ........................................... 142
5. Discussion .................................................................................................................................. 146
5.1 Qualifying the research context ................................................................................................. 146
5.2 Methodology .............................................................................................................................. 147
5.2.1 Analysis of QRD template development up to the present day ................................................. 147
5.2.2 The use of templates for the package leaflet in EU and non-EU countries................................ 148
5.2.3 Evaluation of QRD template implementation in package leaflets of centralised approved
medicines ................................................................................................................................... 149
5.2.4 Study design of the readability test involving QRD template version 8, its predecessor and a
model template version .............................................................................................................. 150
5.2.5 Development of package leaflets and questionnaires for the written readability test ................ 152
5.3 Comparison of the European Union QRD template to templates used in non-EU countries .... 152
5.4 Comparison of comprehensibility, location of information and satisfaction with each package
leaflet tested in the readability test ............................................................................................. 155
5.5 Analysis of content, comprehensibility and locatability of information in the QRD template .. 157
5.5.1 Comprehension and location of information at the start of the QRD template for the package
leaflet.......................................................................................................................................... 157
5.5.2 Comprehension and location of information in section 1 of the QRD template for the package
leaflet.......................................................................................................................................... 159
5.5.3 Comprehension and location of information in section 2 of the QRD template for the package
leaflet.......................................................................................................................................... 161
5.5.4 Comprehension and location of information in section 3 of the QRD template for the package
leaflet.......................................................................................................................................... 165
IV
5.5.5 Comprehension and location of information in section 4 of the QRD template for the package
leaflet.......................................................................................................................................... 166
5.5.6 Comprehension and location of information in section 5 of the QRD template for the package
leaflet.......................................................................................................................................... 171
5.5.7 Comprehension and location of information in section 6 of the QRD template for the package
leaflet.......................................................................................................................................... 171
5.5.8 Comprehension and location of information regarding tablet divisibility ................................. 172
5.5.9 Effects of demographic factors on participants ability to comprehend and locate information . 172
5.6 Global aspects relating to the QRD template ............................................................................. 173
5.7 Summary of advantages/disadvantages/significant differences between templates .................. 175
5.7.1 Comparison of QRD template 7.3.1 and 8 ................................................................................. 175
5.7.2 Comparison of model template and QRD template 8 ................................................................ 182
5.8 Future perspectives to improve the QRD template .................................................................... 189
6. Summary .................................................................................................................................... 192
Literature ................................................................................................................................................... 193
List of tables .............................................................................................................................................. 211
List of appendices ...................................................................................................................................... 216
Appendices ................................................................................................................................................ 218
Curriculum vitae ........................................................................................................................................ 273
Erklärung zur Anfertigung - Verfassererklärung ...................................................................................... .274
Acknowledgements ................................................................................................................................... 275
V
List of abbreviations
ACE inhibitor Angiotensin-converting-enzyme inhibitor
ADEC Australian Drug Evaluation Committee
AMG Arzneimittelgesetz (German Drug Law)
AMIS Arzneimittel-informationssystem (comprehensive drug information
system)
AMZV Arzneimittel-Zulassungsverordnung (Marketing Authorisation
Regulations in Switzerland)
APAC Australian Pharmaceutical Advisory Council
ASMI Australian Self Medication Industry
ATC code Anatomical Therapeutic Chemical code
BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute
for Drugs and Medical Devices)
BPI Bundesverband der Pharmazeutische Industrie (German Pharmaceutical
Industry Association)
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
CDRH Center for Devices and Radiological Health
CHMP Committee for Medicinal Products for Human Use
CMDh Co-ordination Group for Mutual Recognition and Decentralised
Procedures - Human
CMI Consumer Medicine Information/Consumer Medication Information
CPI Consumer Product Information
CVM Center for Veterinary Medicine
DC Decentralised
DE German
e.g. For example
EC European Commission
EEA European Economic Area
EEC European Economic Community
EMA European Medicines Agency
EN English
EPAR European Public Assessment Report
et al. et alli (and others)
etc. et cetera
VI
EU European Union
FDA Food and Drug Administration
HWG Heilmittelwerbegesetz (German drug advertisement law)
IKS Interkantonale Kontrollstelle (Intercantonal office for the control of
medicines in Switzerland)
Info Information
KPAV Komplementär- und Phytoarzneimittelverordnung (Ordinance of the
Swiss Institute of Therapeutic Products concerning simplified Marketing
Authorisations for Complementary and Herbal Medicinal Products)
MAH Marketing Authorisation Holder
MCA Medicines Control Agency
MDA Medical Devices Agency
MedDRA Medical Dictionary for Regulatory Affairs
MedGuide Medication guide
Medsafe Medical Devices Safety Authority
MHRA Medicines and Healthcare products Regulatory Agency
min. Minimum
max. Maximum
MR Mutual recognition
n Number
N.B. nota bene (note well)
NCPIE National Council on Patient Information and Education
NDPSC National Drugs and Poisons Scheduling Committee
No. Number
n.s. Not significant
NSAIDs Non-steroidal Anti-inflammatory Drug
NSAR Nicht-steroidale Antirheumatika (non-steroid antirheumatic drug)
OTC Over-the-counter
p Probability
PDF Portable Document Format
PHARM Pharmaceutical Health and Rational use of Medicines
Ph. Eur. Pharmacopoea Europaea
PI Product Information
PIL Patient Information Leaflet
PPI Patient Package Insert
VII
PRAC Pharmacovigilance Risk Assessment Committee
pt Point
QRD Quality Review of Documents
QUM Quality Use of Medicines
Rx Prescription only medicine
SHP Text verification tool Schlafender Hase und Partner text verification tool (software programme)
SmPC Summary of Product Characteristics
SOC System organ classes
SPSS Statistical Package for the Social Sciences (software programme)
SUSMP Standard for the Uniform Scheduling of Medicines and Poisons
TGA Therapeutic Goods Administration
UK United Kingdom
VAM Verordnung über die Arzneimittel (Pharmaceuticals regulation)
1
1. Introduction
Package leaflets enclosed in medication packages are an important source of information for patients or
carers about a particular medicine, whether prescribed or bought over-the-counter1-3
, and should be read
before starting treatment and while taking the medication. In addition to providing vital information on
indications, contraindications, side effects of the medication, they should also motivate patients to actively
participate in their treatment4.
Improved levels of patient satisfaction have been recorded for patients who received a package leaflet with
their medicine5. They also improve patients' knowledge of how to take their medicines correctly
5, raise
awareness of potential side effects5,6
and generally improve compliance7. One study showed that patients
who had received a patient package leaflet reported the same number of side effects as those who had not,
but those who had received information were more likely to attribute the experienced reactions to the drug
whether the particular side effect was listed or not6. However, it has been reported that the patient
information leaflet is read by only about 70 - 80 % of patients1,8
and few request more specific information
on their own initiative9. It is well known that patients forget or misunderstand much of what is said during
consultation with a doctor or pharmacist and it has been found that on average patients had forgotten half
of what the doctor told them within 5 minutes of leaving the surgery10
. A survey with 154 patients showed
that although 90 % received verbal information about the treatment regimen, fewer were told how to take
the drug or the duration of treatment9. The package leaflet is therefore a vital source of information for
when the patient returns home following a doctor’s consultation9. The situation does arise, however, that
many patients are subsequently deterred from taking the medicine as the content of the leaflet made them
afraid of the treatment1,8,11
. Specialists have reported that patients frequently have less confidence in their
medicine after reading the package leaflet12
. The consequence of ‘less confidence’ in a particular medicine
due to the complex and detailed information contained in a package leaflet can lead to non-compliance
which can have major negative health and economic implications. On one hand this may be via product
loss, as shown by a German study in 1988 and repeated in 1998 which revealed that, although prescription
charges had increased during the 10 year period, that the amount of unused drugs brought back to the
pharmacies had actually increased13
. On the other hand, non-compliance can also indirectly have monetary
effects through the complication of disease management14
. Non-adherence is multi-faceted in the home-
setting and often involves using more or less than the prescribed dose, completely not taking certain
medicines, taking an extra dose, using an unauthorised medication or taking medication at the wrong
time15
. Although a patient’s ability to abide by a certain prescribed treatment regime may be compromised
if they cannot understand basic information about the prescribed medicine, other factors such as the
perceived severity of the illness and social circumstances may also have an effect15
. Not understanding
how to take a medicine properly can also lead to avoidable and possibly serious side effects occurring. In a
2
large scale study on adverse drug reactions as the cause of hospital admission in the United Kingdom, it
was shown that up to 70 % were either possibly or definitely avoidable16
. Incorrectly used drugs are also
more frequently involved in adverse drug reactions than those which are correctly used17
. Improper use
was caused by drug interactions, off-label use, incorrect duration and inadequate dosage and
contraindications. Reading the package leaflet is therefore vital for safe and effective medication use.
Therefore, the package leaflet must be understandable to a wide spectrum of ages and for all levels of
education, but one survey showed that one in five users found them to be not comprehensible18
. This is a
problem which has been identified in the majority of package leaflets. Regardless of the focus in the
package leaflet, they require relatively high reading skills that may not exist in a large proportion of their
target populations19
. Many of the terms included in a package leaflet are also not clear enough for a patient
to understand, for example ‘high doses’ or ‘long term use’20
. Not all sections of the package leaflet are of
equal comprehensibility for the user. In a Swedish study of 30 randomly selected leaflets, it has been
found that although patients could recognise and comprehend various information items in the information
leaflet, certain sections, namely ‘risks of interactions’ and ‘contraindications’ were poorly understood21
.
This was suggested to be due to the complexity of the information contained in these sections. A further
study in Germany to assess patients’ knowledge on anticoagulants also revealed that drug-drug and drug-
food interactions were least understood22
.
Some sections of the package leaflet are generally considered to be less important than others by the
reader, for example, the names and addresses of the pharmaceutical company and manufacturer23
. In
contrast, the indication, dosage instructions and side effects were classed as ‘very important’. Readers of
package leaflets in Belgium were found to focus mainly on adverse effects (88 %), how to take the
medicine and how much to take (85 %) and contraindications (82 %)8. A study in which patients were
asked to put the importance of the sections of the package leaflet in order of precedence showed that the
indication should start the leaflet followed by dose instructions, composition, warnings for use,
contraindications, interactions and side effects23
. This does not completely match the legally defined
sequence of sections, as using a logical order requires that contraindications and special warnings must be
provided before patients use the dosage instructions23
. However, the current order of information does
better reflect patients’ requirements than the version before Directive 2004/27/EC24
came into force12
.
The content and presence of a package leaflet for a particular medicine was originally determined by the
national ruling of the country where it was brought into circulation. This later changed for countries in the
European Union (EU) as European legislation was put into place to govern the content and order of
information. This marked a major change in the status of the package leaflet in the affected countries. In
3
1992, the European Community adopted Directive 92/27/EEC25
, which stated that a patient information
leaflet (PIL) must be provided with all medicines distributed within the European Union. This legislation
was implemented on January 1st 1994 and made the presence of a package leaflet mandatory from January
1999. Package leaflets in some European countries such as Germany had been firmly established since the
1960s, but other countries introduced them comparatively recently. In Belgium, regulations for the
mandatory inclusion of a package leaflet had existed since 198426
and in France since 198527
, while the
United Kingdom only made them compulsory in 1999 due to European Legislation. Outside the EU, in
Switzerland the presence of a patient package insert (PPI) was made a requirement from January 1st
198926
. In Australia, consumer product information (CPI) had to be provided for all new drugs by January
1993 and for all existing drugs by January 200228
. During the late 1960s, the FDA in the United States of
America first introduced patient package inserts but only for certain asthma medications and oral
contraceptives27
. It was only in 2006 that a major revision regarding patient package insert guidelines was
made by the FDA.
Although package leaflets were already in use in the 1960s in Germany, original German Drug law
(Arzneimittelgesetz) from 196129
only required that the name of the medicine and manufacturer, contents
of the packet, pharmaceutical form, application method and active ingredients had to be noted on the outer
packaging and container, meaning at this time that only certain companies provided a package leaflet with
their product. In 1973, the German Pharmaceutical Industry Association (Bundesverband der
Pharmazeutische Industrie (BPI)) published a guideline regarding package leaflets which was made
effective in 197430
. This guideline was largely implement into German Drug law from 197631
, where § 11
made inclusion of a package leaflet mandatory, although its content was intended for patients, doctors and
chemists. This was found to cause great difficulties in comprehension by the patient due to the use of the
specialist medical terminology in these leaflets4. A separation of information for patients and healthcare
professionals only came about in 1986 through application of further changes in national drug law32
.
Directives adopted by the European Community require European Member states to implement their
provisions nationally. The European Directive 65/65/EEC33
from January 1965 provided the first laws
within the European Union for the production and distribution of medicinal products in order to safeguard
patient health. As already stated above, the inclusion of a package leaflet was not mandatory at this time
although the particulars which had to appear on the containers and outer packages of medicinal products
were mentioned in Articles 13 - 20. Directive 65/65/EEC33
was amended in 1975 by Directive
75/319/EEC34
. It was noted in Article 6 that, where a leaflet is enclosed, all information in the leaflet must
be provided in accordance with Article 4 of Directive 65/65/EEC33
. Minimal criteria were defined in
Article 6 for the contents of the package leaflet, such as therapeutic indications, contraindications and
4
directions for use of the product although its presence was to be decided by the relevant member state.
Directive 89/341/EEC35
amended directives 65/65/EEC33
and 75/319/EEC34
and the new subparagraph in
Article 6 stated 'The inclusion of a package leaflet in the packaging of medicinal products shall be
obligatory unless all the information required by this Article is directly conveyed on the container itself
and the outer packaging’.
With the introduction of European Directive 92/27/EC25
in 1992, further particulars to be described in the
package leaflet and on the outer and immediate packaging were defined. Article 7 determined the order
and contents of the package leaflet and stated that symbols and pictograms could be used in the package
leaflet to clarify certain information, but all elements of a promotional nature must be excluded. Article 8
stated that ‘The package leaflet must be written in clear and understandable terms for the patient’25
. In
Article 12 of this directive it was announced that the Commission was going to publish guidelines,
amongst others concerning especially ‘the legibility of particulars on the labelling and package leaflet’. It
was originally planned in Article 12 (2) that these guidelines would be adopted in the form of a directive
but this never happened. Rather, the first Readability Guideline was published after approval by the
Pharmaceutical Committee of the European Commission in September 199836
with the proposed date for
coming into operation in January 1999. As it never became enforced as a directive it remained a
‘Guideline’ according to Article 249 of the ‘Consolidated versions of the treaty on European Union and of
the treaty establishing the European community’ where it is defined that recommendations and opinions
have no binding force37
. The Readability Guideline was however still updated in January 200938
. The
purpose of the guideline was to lay down general principles to help pharmaceutical companies make the
labelling and information in the package leaflet legible and comprehensible for the patient. The first
Readability Guideline edition in 1998 contained a model template for the package leaflet and both editions
included a means of testing readability to examine whether the user can find and understand appropriate
information in the leaflet, and act on it accordingly.
Directive 92/27/EC25
was later revised by Directive 2001/83/EC39
in 2001 which dealt mainly with
discrepancies between certain national rulings, especially those regarding medicinal products, and
attempted to assemble them in a single text in order to safeguard public health within the member states of
the European Community. The information that inclusion of package leaflets was obligatory was moved
from Article 6 in Directive 92/27/EC to Article 58 in the new directive. Article 59 of Directive
2001/83/EC39
stated that the ‘package leaflet shall be drawn up in accordance with the summary of
product characteristics’ and then provided a list of the content and order. Article 63 (2) included the
following ruling ‘The package leaflet must be written and designed to be clear and understandable,
enabling the users to act appropriately, when necessary with the help of health professionals. The package
5
leaflet must be clearly legible in the official language or languages of the Member State in which the
medicinal product is placed on the market’. Should a package leaflet not conform to the requirements of
Directive 2001/83/EC, market authorisation may be refused.
Directive 2004/27/EC24
subsequently amended Directive 2001/83/EC39
, which resulted in several changes
being introduced influencing the order of the contents of the package leaflet. The status of the package
leaflet also changed following implementation of Directive 2004/27/EC24
that made user testing a must for
all package leaflets, which studies have shown to be beneficial in ensuring that leaflets are patient
orientated40
. Article 59 (3) thus included the following statement ‘the package leaflet shall reflect the
results of consultations with target patient groups to ensure that it is legible, clear and easy to use’ while
Article 61 (1) declared regarding the package leaflet that ‘The results of assessments carried out in
cooperation with target patient groups shall also be provided to the competent authority’.
The latest changes to the package leaflet within the European Union were caused by implementation of
new European pharmacovigilance legislation which became applicable in July 2012. Regulation (EU) No.
1235/201041
and Directive 2010/84/EU42
, are intended to improve patient safety and health by
encouraging patients to directly report adverse drug reactions to the relevant national authorities.
Introduction of a black symbol at the start of the package leaflet defined in the Implementing Regulation
(EU) No. 198/201343
was also intended to show patients whether the medicinal product described in the
package leaflet is subject to additional monitoring.
With the intention of harmonising the structure and content of patient information in the Europe Union
and connected countries (Norway, Liechtenstein and Iceland), the Working Group on the Quality Review
of Documents (QRD) was established in June 1996 by the European Medicines Agency (EMA)44
who
published the first edition of the QRD template in the same year. The QRD template, which is based on
Article 65 of Directive 2001/83/EU39
, covers general requirements for the summary of product
characteristics, labelling of the product and the package leaflet of medicines. Thirteen updates followed
since the first edition of the template for medicines approved via the centralised procedure up to the latest
version 9 in March 2013. The QRD template itself is a text framework which provides headings for
paragraphs and sub-paragraphs including standard statements applicable for the broad range of distributed
medicines. Medicine specific information is inserted into this text frame by the pharmaceutical companies.
The QRD template for centralised procedures is available in the 23 official EU languages with the addition
of Icelandic and Norwegian and aims to support the pharmaceutical industry in providing user friendly
product information. Centralised procedures came into operation in 199545
allowing applicants to obtain a
marketing authorisation that is valid throughout the EU, Norway, Liechtenstein and Iceland. A slightly
6
modified version of the QRD template for centrally approved medicines is available for package leaflets
approved within mutual recognition (MR) and decentralised procedures (DC)46
. More extensive templates
are also provided for certain product groups such as radiopharmaceuticals47
. Using the QRD template has
the advantage that patients find identical standardised headings and general texts, including the same order
of information in package leaflets in each European Union member state plus the three above mentioned
associated countries44
.
According to the ‘Consolidated versions of the treaty on European Union and of the treaty establishing the
European community’, article 249, the QRD template is also only a guidance document and therefore not
legally required to be implemented into practice37
. However, the QRD template states on the first page of
the annotated QRD template version 948
that standard statements given in the template ‘...must be used
whenever they are applicable.’ Deviation is possible in certain cases to accommodate specific medicinal
product needs and will be considered on a case-by-case basis46
. Although the revised Readability
Guideline from 2009 contains no model template, Marketing Authorisation Holders are told to use the
QRD templates provided by the EMA. Newer versions of the QRD template use a bracketing convention
and different colour text for certain information: curly brackets define information which must be filled in,
pointed brackets are for text which can be selected or deleted as appropriate, and text which is not
contained in brackets must be used. Throughout the document orange coloured text is used to cross-refer
to sections of the SmPC and green text is used for explanations.
During development of QRD template version 8 (for centralised approved medicines) and version 2 (for
medicines authorised by other procedures) in 2011, headings and mandatory texts underwent major
changes based on information gained from user testing and feedback from various sources, such as
agencies, the pharmaceutical industry and academia as well as patient and consumer groups49
. The above
mentioned user testing results are a collection of reported specific problems identified in the previous
QRD template version 7.3.1, although the methods used and the data generated which were analysed to
come to these conclusions remain unpublished. The most recent QRD template version 9 provided several
further text additions as a result of the latest pharmacovigilance legislation41,42,50
. Despite these significant
extensive changes applicable for all package leaflets in the European Union, relevant studies have not
been carried out. Furthermore, since the first QRD template was published in 1996, its volume has
expanded48,51
. However, the effect of this increased volume of QRD template text has not been addressed
although previous studies have shown the advantages of a short model template of around 200 words,
mainly through avoiding repetitions and long sentences52,53
. Moreover, use of the QRD template is one
main reason for increasing package leaflets’ text volume with the negative outcome of reduced locatability
7
of provided information, decreased motivation to read the package leaflets and increased mistrust in using
required medicines after reading the patient information54,55
.
8
2. Objectives
A main focus of the project is whether the extensive changes published in the QRD template version 856
provide advantages in readability and understanding for the patient. Therefore, the following main points
regarding the QRD template were addressed in detail:
1. Development and implementation of the QRD template:
How has the QRD template developed from its initial form to the present day?
How are QRD template headings and text elements used in general?
How are specific aspects and text blocks implemented?
2. The use of templates for the package leaflet in European and non-European countries:
Which templates in German or English exist for the package leaflet in European and non-
European countries?
Which legal requirements influence the content and structure of package leaflet
templates?
How do the templates compare to each other in terms of structure and content?
3. Readability test of the QRD template 8, its predecessor and a model version:
How is the locatability and comprehensibility of the template texts?
How does the template influence the locatability and comprehensibility of medical
specific information?
Are patients satisfied with the template information provided or where do they see room
for improvement?
9
3. Materials and methods
3.1 Analysis of QRD template development up to the present day
QRD template versions 1 to 7.3.1 in English were kindly provided by the EMA, while versions 8 and 9
were downloaded from the EMA website46,48,51
. The QRD templates for radiopharmaceuticals57
as well as
that included in the first Readability Guideline published 1998 were also included in the analysis36
.
The black QRD template text in English for package leaflets of centralised approved over-the-counter
(OTC) medicines was analysed regarding the number of words using the word count tool from Microsoft
Office Word 2007. The bracketing convention in the template whereby information in pointed brackets
can be optionally selected or deleted allows for large amounts of black text to be omitted. Therefore, for
the minimum possible word count, all optional information was deleted including storage conditions
proposed for the package leaflet in section 5. The maximum word count adopted the opposite principle
and counted the number of words when all QRD template texts printed in black are counted. The list of the
29 local representatives was not considered in the analysis of the maximum word count. In cases where
‘<take> <use>‘ or similar options were provided, only one word of both possibilities was counted, as only
one term should be used in the package leaflet.
In addition, the number of long sentences, repetitions and abbreviations used in the black QRD template
text was calculated. According to the Readability Guideline of 1998, a sentence was assessed as a ‘long
sentence’ if it contained more than 20 words36
.
Furthermore, the information in black QRD template text of each section was analysed to illustrate the
QRD template changes and development up to the current date. The orange text for cross references to the
SmPC in the QRD template or the green text used for explanations were not taken into account in this
investigation.
3.2 The use of templates for the package leaflet in EU and non-EU countries
One component of the project was to analyse package leaflet templates from different countries, and to
investigate the structure and content of these templates. An internet search was initiated to identify the
relevant authorities responsible for granting marketing authorisations for pharmaceutical products in
English and German speaking countries. The following main criteria were used for the information
selection:
Inclusion of EU and non-EU countries where templates were used for the package leaflet;
Templates which were available in German or English;
Search for legal requirements influencing the content and order of the templates in the selected
countries;
10
Search for national guidelines providing recommendations for the design and content of the package
leaflets;
Search for the history behind the development of templates.
Information in the form of links to guidelines or directives provided on the internet pages of the country
specific authorities as well as internet research was used to analyse the history, regulations, content and
structure of existing package leaflets and templates. Available templates from each country were then
compared to the QRD templates 8/9 in terms of the sections contained, headings used and compulsory
statements. Subsequently, templates from the selected counties were compared to each other.
3.3 Analysis of QRD template implementation in package leaflets of centralised approved
medicines
All package leaflets in the English language for medicines granted a centralised authorisation and
available on the EMA website58
at a defined date were downloaded and used to analyse how the QRD
template is implemented in practice. Medicines which were withdrawn post-approval, suspended or
refused were not used in the study. This was repeated twice with a time gap of one year between each
download.
For the second and third downloads, only package leaflets which were present in the first download and
had been updated were extracted. The data for the unchanged package leaflets were however also
integrated into the dataset for analysis in the second and third downloads to investigate how rapidly and to
what extent the QRD template had been implemented within the past year.
The package leaflets from each download in the form of PDF files were subsequently converted into
Microsoft Office Word 2007 documents for further analysis using the software Adobe Acrobat 9 Standard.
The following catalogue of criteria was used to assess each package leaflet and information was coded and
analysed using a Pivot table in Microsoft Excel 2007:
Type of product: pharmaceutical form described in the package leaflet, prescription status, ATC
code and grouping by considering the first letter of this code.
Number of package leaflet words using the tool ‘Word count’ of the Microsoft Office Word 2007
program: This total word count comprised all information contained in the package leaflet including
any additional information present after section 6 of the package leaflet. In addition, leaflets were
noted which contained special use instructions for patients, or extra information for health
professionals at the end of the leaflet after section 6, and the number of words this information
11
contained, was counted to allow further analysis of the contribution to the total amount of text that
this information is responsible for.
Number of QRD template words using the tool ‘Word count’ of the Microsoft Office Word 2007
program: All information was deleted from the package leaflet which was not recognised to be from
the black printed QRD template text to measure the volume of text arising from the QRD template.
The name of the medicine at the top of the leaflet, and where it was used to replace ‘X’ in template
texts, was also not removed.
QRD template version: This was determined by examining the wording contained in the contents
list, information box and side effects section which differs between template versions.
Presence of the contents list
Presence of the black symbol from QRD template 9
Information contained at the start of the leaflet: Since implementation of QRD template 751
, four
points containing one to three sentences are potentially present in the information box. For each
leaflet it was noted which of the following four points were present:
– ‘Keep this leaflet. You may need to read it again’
– ‘If you have any questions ask your <doctor> < or > <pharmacist> (additionally <or nurse>.’
in QRD templates 849
and 948
). A subanalysis was also carried out as to whether only doctor
was mentioned, doctor and pharmacist and/or nurse or combinations of other terms.
– ‘This medicine has been prescribed for you (additionally ‘only’ in QRD templates 849
and 948
).
Do not pass it on to others. It may harm them, even if their symptoms are the same as yours’
(prescription only medicines) or ‘You must contact a doctor if your symptoms worsen or do
not improve’ (non prescription medicines) (QRD template 751
); Do not pass it on to others. It
may harm them, even if their signs of illness are the same as yours (prescription only
medicines) or ‘You must talk to a doctor if you do not feel better or if you feel worse <after
{number of} days> (non prescription medicines) (QRD templates 849
and 948
).
– ‘If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.’(QRD template 751
); ‘If you get any side effects, talk to
your <doctor> <,> <or> <pharmacist> <or nurse>. This includes any possible side effects not
listed in this leaflet’ (QRD templates 849
and 948
). The prescence of sentence ‘See section 4’
from QRD template 948
was also noted.
12
Reference to location of list of excipients: In section 2 of the package leaflet, the patient is told not
to take the medicine if they are ‘allergic (hypersensitive)’ in QRD template 751
and just ‘allergic’ in
QRD templates 849
and 948
to the active ingredient or any of the excipients. The package leaflets
were examined to see whether the patient was provided guidance in the contraindication section on
where to find this information within the leaflet.
The method of presenting side effects: Whether a table to describe the frequency classes was
present at the start of section 4, or if the frequency was described as part of the side effect list was
noted. The description type of frequencies was also coded. The use of MedDRA SOCs and whether
the most serious side effects were located at the start of the section were additionally assessed.
List of Marketing Authorisation Holders’ representatives: The presence or absence of the list was
noted. The number of words in this list was determined again using the word count tool from
Microsoft Office Word 2007. Furthermore, which information was present in this list was recorded:
MAH representative name, post address, telephone number, email address.
Subanalysis relating to template wording use: To examine how widely headings and standard
statements from QRD templates 7 and 8/9 were used in package leaflets, an additional subanalysis
involving aspects of the templates which differ between QRD templates 7 and 8/9 was undertaken.
A yes or no decision was made as to whether the elements of either template 7 or 8/9 shown in table
1 were present in the examined leaflets.
As it was not possible to convert all downloaded package leaflets into word documents in the first
download, it was analysed whether the investigated group of package leaflets was representative of the
total sample which were available for centralised approved procedures on the EMA website. The analysed
package leaflets were therefore analysed to the total sample group with respect to:
- sales status: prescription only or OTC
- indication as defined by the first letter of the ATC code
- pharmaceutical form
The pharmaceutical forms were divided into 5 main groups: film-coated tablets, parenteral administration
forms (injections and infusions), all other tablets (including dispersible, buccal, prolonged release), all
capsules (including soft, hard, gastro-resistant) and others (nasal spray, eye drops, transdermal plasters,
gases). Then the percentage of the products which fell into each of the three categories described above
was determined for the group of analysed package leaflets and the package leaflets of the complete sample
set on the EMA website. Subsequently, the upper and lower limits of the 95 % confidence interval for the
percentage of examined package leaflets was calculated using the following formula:
13
Upper limit: gu = (rh(A) + u1-α/2 x (rh(A) x (1 – rh(A)) / n)1/2
Lower limit: gu = (rh(A) - u1-α/2 x (rh(A) x (1 – rh(A)) / n)1/2
rh(A) = relative frequency of an observed parameter from the total sum
α = 1 – observed confidence interval (for the 95 % confidence interval α = 1 – 0.05 = 0.05)
u1-α/2 = Quantile of the normal distribution (for the 95 % confidence interval u0,975 = 1.96)
n = total number
Table 1: Elements contained in QRD templates 7 and 8/9
Template heading/standard
text
QRD template 751
QRD templates 849
/948
Contraindication sentence in
section 2 under ‘Do not
<take> <use> X:
if you are allergic
(hypersensitive) to ….
if you are allergic to…
Warnings and precautions
subheading
Take special care with X Warnings and precautions
Standard statement regarding
interactions with other
medicines
Please tell your <doctor> <or>
<pharmacist> if you are
<taking> <using> or have
recently <taken> <used> any
other medicines, including
medicines obtained without a
prescription.
<Tell your <doctor> <or>
<pharmacist> if you are <taking >
<using>, have recently <taken>
<used> or might <take> <use> any
other medicines.
Subheading for interactions
with food and drink
<Taking> <Using> X with food
and drink
X with <food> <and> <,>
<drink> <and> <alcohol>
Subheading regarding
pregnancy, breast-feeding,
fertility
Pregnancy and breast-feeding Pregnancy <and> <,> breast-feeding
<and fertility>
Optional statement for
pregnant or breast-feeding
women
<Ask your <doctor> <or>
<pharmacist> for advice before
taking any medicine>
<If you are pregnant or breast-feeding,
think you might be pregnant or are
planning to have a baby, ask your
<doctor> <or> <pharmacist> for
advice before taking this medicine>
Excipients warnings
subheading
Important information about
some of the ingredients of X
X contains {name the excipient(s)}
14
Template heading/standard
text
QRD template 751
QRD templates 849
/948
Side effect warning sentence
at the end of section 4
If any of the side effects get
serious, or if you notice any
side effects not listed in this
leaflet, please tell your
<doctor> <or > <pharmacist>
Template 8: If you get any side
effects, talk to your <doctor> <or>
<,>pharmacist> <nurse>. This
includes any possible side effects not
listed in this leaflet
Template 9: Reporting of side
effects
If you get any side effects, talk to your
doctor or pharmacist. This includes
any possible side effects not listed in
this leaflet. You can also report side
effects directly via the national
reporting system listed in Appendix
V. By reporting side effects you can
help provide more information on the
safety of this medicine.
15
3.3 Readability test of the QRD template version 8, its predecessor and a model version
3.3.1 Development of package leaflets in three different templates
To achieve the aims set out in chapter 2, package leaflets were developed using the QRD template for
centralised approved medicines version 7.3.1 or 8 or a model template with around 200 words52
which had
been tested in a previous study and is based on the QRD template. The QRD template for centralised
procedures was chosen to enable inclusion of the 29 optional representative addresses of the marketing
authorisation holders. Each leaflet was printed with an identical layout and design to enable comparison
between template versions and ensure standardised conditions. The maximum text version was used for
both QRD templates according to the bracketing convention. The BfArM sample text for the prescription
only ACE-inhibitor enalapril59
, which was publicly available at the start of the project and had been used in
previous studies52,53
, was chosen to fill in the text frameworks (appendix 1). Versions of the leaflet were
created in German which contained the full length of the sample text provided by BfArM using the three
templates (see appendices 2, 3, and 4 for long German package leaflets). This text was then shortened and
optimised - named in this work as short text throughout - to contain identical information but as a series of
concise bullet points in the same templates, to provide an easily readable and comprehensive text (see
appendices 5, 6 and 7). This method ensured comparability to similar texts with a model template tested in
a previous study which had been improved in terms of comprehensibility53
. These three short leaflets were
then translated into English (see appendices 8, 9 and 10). Three groups of package leaflets were thereby the
result; long and short text versions with the three templates for testing in Germany, and a short text version
for use in England. The template text varied in each package leaflet group whereas the package leaflet text
always remained the same.
In the interaction section contained in package leaflet section 2, colons were used in the English and
German short version of the leaflets with the model template and QRD 7.3.1 to separate the name of the
active ingredient - which may interact with enalapril - and the patient friendly explanation. In leaflets with
template version 8, the name of the active ingredient was listed first and the patient friendly explanation
was enclosed in brackets according to the recommendations of this template version.
Different methods for the description of the frequencies of side effects were used according to the
template versions: a table at the beginning of the provided side effects was used in leaflets with QRD
template version 7.3.1, and an explanation at the beginning of each side effect group in that using the
model template and QRD template version 8. In leaflets with version 8, side effects were divided into
serious and other - this was not the case in the other template versions. The model template accentuated
serious side effects in bold and did not include an extra paragraph for countermeasures in the case of
serious side effects in section 4 as this information was integrated into the list of side effects.
16
In section 6 of the shortened text versions of both languages, ‘other ingredients’ were listed alphabetically
rather than according to the amount contained in the described enalapril tablets, and E-numbers and the
abbreviation Ph.Eur nomenclature were not included. Leaflets with QRD templates 7.3.1 and 8 contained
the list of 29 representatives of the MAH holder in section 6.
A slight difference exists in QRD template version 8 in section 2 between translations whereby the cross-
reference to other ingredients in section 6 is given in brackets in the English QRD template version, but
not in the German one, where it is included in the running text.
During the preparation phase, leaflets were carefully edited for spelling and grammatical errors and
checked that they were compliant to the relevant template. The word texts were then type-set into a mock-
up format using Adobe InDesign CS4 software. This program allowed the files to be converted into PDFs
for printing in a typical form which is used for package leaflets that are readability tested and
subsequently distributed on the market. To avoid errors, the Schlafender Hase Text verification Tool 5.1.1
was used to compare the prepared PDF documents with the original Word texts. Identical type size, paper,
layout and design were used in each package leaflet and questionnaire in both countries.
3.3.2 Development of the questionnaire
A written readability test questionnaire was developed based on those which had been used and tested in
previous studies52,53
. The questionnaire contained an introductory letter followed by sections for:
a) demographic data
b) rendition of the package leaflet’s contents
c) participant’s personal opinion on the leaflet.
Demographic data which was to be filled in by the participants after receiving the questionnaire included
age, level of education, postcode, reading habits and the number of medicines taken at the time of the
study for each participant.
The second part of the questionnaire for ‘rendition of the package leaflet’s content’ assessed using the
written readability test, whether participants could find certain information contained in the package
leaflet and know how to act on it. The 26 questions in this section were worded to test key template text
messages rather than knowledge on the active ingredient of the medicine itself. Care was taken with the
formulation of the questions by using other wording than that contained in the package leaflet to avoid
17
information being found simply by word comparisons. At least one question was included relating to each
testable template section heading or standard template sentence in the package leaflet. As the
recommendations in the green explanatory text in the template were also to be tested, for example, the
suggested method of describing side effect frequencies was tested for comprehensibility. More than one
question was present for key safety messages such as how to act when side effects occur. Considerably
less content related questions than in this study are usually used in a readability test where according to
the Readability Guideline38
, 12 - 15 questions are sufficient, although this is based on a test involving an
interviewer. A conscious decision was made to include more questions than recommended, as the test
described in this study did not involve an oral interview and was designed to test the template text
meaning sufficient questions were required to test all sections (personal communication, Dr. J. Fuchs).
No time limit was set in which this section had to be completed, but participants were instructed to note
the time when they started answering the content questions, and then again when they had finished. The
time taken to answer each individual question was not measured.
Three categories were used for analysis of the data relating to the content questions:
1. Correct answer
2. Wrong answer
3. Answer not found (if an answer was not found, a box was provided which could be ticked by the
participants)
The third part measured personal opinions to 15 statements regarding readability, length of information,
comprehensibility, layout and confidence in the medicine which were intended for assessment by
participants using a five point Likert scale shown in the right column of table 2. This scale has previously
been used and found to be acceptable60
. In an extra section at the end of the questionnaire, participants were
then asked to describe in free text their opinion on the read package leaflet, and what, if anything should be
added or deleted. The questionnaires can be seen with the correct answers in appendices 11 and 12. The
English questionnaire was a faithful translation of the German version.
Before the first readability test round was carried out, a pilot test was performed with the prepared leaflets
and questionnaires to ensure that they worked in the practice, even though this is not compulsory for the
written readability test method61
. In this pilot test, two people read each version of the short package
leaflet in England and Germany, and four people read the long BfArM text versions of the leaflet in
Germany. As the questionnaires and short package leaflets are direct translations of each other, four
people had therefore read each short version of the leaflet, and four people the long BfArM text version in
each of the three templates. The order in which each of the three package leaflets in a group was read, was
18
random. An approximately 10 day time interval was maintained between reading each package leaflet and
participants subsequently filled in the questionnaire. A 10 day time interval was chosen to rapidly gain
feedback as to whether the questionnaire was suited to testing the package leaflets. The answers provided
were subsequently analysed to see if either the printed layout of the package leaflet in terms of changing
line-breaks or positioning of sections, or the questions contained in the questionnaire needed any
alterations as they led to misunderstandings. For example, finding information for a certain side effect
involving the liver was found inappropriate as liver-related problems were also contained in other sections
of the package leaflet.
3.3.3 Study execution
Readability testing is the current gold standard used within the European Union to evaluate package
leaflets. The written readability test method, also known as the ‘self-completion method’, which is widely
accepted within the European Union61
, was considered to investigate the locatability and comprehensibility
of the template texts. The readability test was carried out using a cross-over study design whereby each
subject had to read all three versions of the leaflet and answer the questionnaire described in section 3.3.2.
A 6 month time interval was applied between testing each template version of the leaflet as this is an
officially recommended time gap between two readability tests carried out with one person62
. To obtain
robust data, it was decided to recruit over 60 participants per package leaflet group as this is three times the
recommended number for a readability test38
. The participants were given the questionnaire with identical
questions in each of the three test rounds per package leaflet group, whereby in each test round the template
varied while the medical specific package leaflet text remained the same.
The selected participants should be representative of everyone who might take a medicine and therefore
during recruiting, participants with a broad range of literacy and age were included as long as they were
considered to be able to independently read the leaflet and answer the questionnaire. Subjects from the
medical profession were excluded from the study. As it is possible that medications are taken
independently by teenagers, they were also included in this study, an additional advantage being that they
are not the target group for enalapril and therefore probably have no previous knowledge of either the
medicine or the indication.
Recruiting of participants was predominantly in the Lichtenfels and Bamberg areas in Germany to test the
German versions of the package leaflets, and in the Cambridge area in England for the English versions.
Subjects were selected randomly and participation was voluntary. Before handing out the package leaflets
and questionnaires, the purpose of the test was explained to the participants, who were also shown the
explanatory notes in the cover letter and instructions at the beginning of the questionnaire. Participants
19
were reassured that neither their memory nor intelligence was being tested and that the leaflet could be
referred to during the answering of the questionnaire.
3.3.4 Statistical analysis
All answers provided in the returned questionnaires for each of the three rounds of the readability test were
coded and entered into an SPSS 15.0 table. Double data entry was carried out to avoid input data errors. For
the demographic data, the average age of the participants involved was calculated as well as the average
number of years at university for those subjects who had been university educated. Minimum and
maximum time in hours that participants spent reading a day, and how long participants occupied
themselves with medical reports a week were also noted.
The calculated medians in percent of the total number of correctly and incorrectly answered questions, as
well as where the information was not found were calculated for each leaflet version. For each individual
question, the percentages of correct and incorrect answers, as well as where the information was not found
for a particular question were calculated for each leaflet and template version. The calculated median was
used again to determine the time needed to answer the questions for ‘rendition of the package leaflet’s
contents’ in order again to avoid negative influences of outliers and extreme values in the analysis.
Significant statistical differences between the three template versions regarding total correct, wrong and not
found answers and locatability time per template in each leaflet group were calculated using the global non-
parametric Friedman test in SPSS followed by the non-parametric Wilcoxon test between paired samples63
.
Subsequently the Holm-alpha correction method was used64
.
It was then investigated whether the template used had influenced whether a question had been answered
correctly or not. Statistically significant differences between the results for each individual content question
between template versions in a group were calculated using the Cochran test as a global test followed by
the McNemar test which compares two single values, and subsequently the Holm-alpha correction method
was used according to Schaffer64
. Any significant influence of demographic factors was examined using
Pearson’s chi-square test in the SPSS program followed by the Holm-alpha correction method according to
Schaffer64
.
Before analysis of participants’ opinions regarding comprehensibility, layout and legibility of the package
leaflet, the answers to 6 of the 15 questions were recoded, as the original question had been worded to
avoid participants simply answering every question with ‘yes’. Following recoding, the calculated medians
were determined for each question (table 2).
20
Table 2: Range for assessment criteria for participants’ opinions on the package leaflet
Range Participants’ opinion
1.00 to 1.50 Yes
1.51 to 2.50 Mostly yes
2.51 to 3.50 Other
3.51 to 4.50 Mostly no
4.51 to 5.00 Not at all
To detect significant differences between the personal opinions about the package leaflet for each template
version used, the non-parametric Sign test for 2 related samples in SPSS was used followed by the Holm-
alpha correction method according to Schaffer64
. Thus, the personal responses regarding each package
leaflet for each question were compared to each other in pairs.
For the four free text questions contained at the end of the questionnaire, the responses provided by the
participants were coded and entered into SPSS. The frequency with which a particular response occurred
for each package leaflet was counted.
21
4. Results
4.1 QRD template development up to the present day
4.1.1 Number of QRD template words for package leaflets of OTC medicines
The first two published versions of the QRD template for OTC medicines included only twelve section
headings which literally reflected the information required by article 7 of Directive 92/27/EEC which was
in force at that time25
. No general advice or subheadings were provided that should be used verbatim in
package leaflets, therefore the number of words used in both template versions was only 94 (shown in the
figure). Although the QRD template version 3 was based on the same directive as both its predecessors, it
had already taken on a form similar to that which we recognise today using mandatory main headings and
subheadings plus general informative phrases. In version 3, the number of main section headings was
reduced to five, the placeholder ‘X’ was used in the template to fill in the name of the medicine, pointed
brackets were used for optional texts and explanations were given in green ink. These changes caused the
number of words to increase greatly as seen in the figure and reflected the package leaflet example of the
first Readability Guideline which was also published in September 1998, as was QRD template version
336
. The increase in the maximum number of words was plainly greater than the minimum number of
words as shown in the figure, a situation which applies up to the QRD template version 948
published in
March 2013. Although the template for radiopharmaceuticals57
cannot be directly compared to those
described as it is for prescription only medicines, it was of interest to see that it contains by far the most
words, the minimum being 762 and the maximum 1154.
QRD template versions 4 to 6.1 were published between August 1999 and July 2004. Template version 6
was the earliest to include information in the package leaflet as required by Directive 2001/83/EC39
. In
version 6.1, orange text was used for the first time to cross-refer to sections in the SmPC which should be
reflected in that particular section in the package leaflet. The QRD template version 7.0 was published in 5
different editions between 2005 and 2010 and was the earliest to be available as an annotated and non-
annotated edition on the EMA website. In the advisory text at the start of QRD template version 7.0
(published July 2005) it was stated that applicants had to make sure that the package leaflet was made
available in formats appropriate for the blind and partially sighted, reflecting Article 56 (a) of Directive
2004/27/EC24
. Furthermore, the new order of information published in this directive was considered, for
example, all ingredients had to be listed in the final section of the package leaflet instead of at the
beginning. QRD template version 8 (published in July 2011) shows many changes in the package leaflet
when compared to its predecessor 7.3.165
. Detailed explanations are given in green text in all sections and
cross references to the relevant sections in the SmPC are provided in orange. Many more subheadings are
present such as regarding use by children and adolescents reflecting changes which were previously made
to the SmPC in QRD template version 7.3.1. This is stated in QRD template version 8 to be an attempt to
22
make it easier for patients to navigate their way through the package leaflet. Pointed brackets are used
more frequently in version 8 meaning that more standard statements are optional than in previous
templates which could result in a reduction in the minimum number of template words required for
package leaflets, but the figure shows the outcome to be the opposite.
Figure: Number of words in the QRD template intended for OTC products
In March 2013, a new QRD template (version 9)48
was published which offered an amendment for
medicinal products which are subject to additional monitoring. This in the form of a black inverted
triangle, and an appropriate related explanatory text. The information box at the start of the package leaflet
should also include a cross-reference to section 4 to aid the user in locating possible side effects. Two
standard sentences in section 4 further encourage users to report any adverse reactions. These new text
passages were due to the implementation of the pharmacovigilance legislation42
. Template version 9 again
increased the number of words contained in the QRD template.
4.1.2 Repetitions, long sentences and abbreviations in the QRD template
Avoid long sentences of over 20 words in length and abbreviations are two recommendations of the first
Readability Guideline of 199836
. Repetitions should also be eliminated as this leads to an increase in the
volume of text. All versions of the template - except 1 and 2 - use sentences of over 20 words and
recurring information. While versions 3 to 6.0 only used one repetition of the same content, this number
0
100
200
300
400
500
600
700
800
900
No
. o
f w
ord
s
Template version (publication date)
Min. words
Max. words
23
increased to two in version 6.1, three repetitions in versions 7.0 to 7.3.1 and four since version 8. A similar
trend was seen in the number of long sentences, with two sentences of over 20 words in QRD template
versions 3 to 6.1 and three in versions 7.0 to 7.3.1. However, versions 8 and 9 showed an improvement
with only one long QRD template sentence.
Abbreviations are only found at the end of the package leaflet in version 7.0, with ‘EMEA’ and from
version 8 ‘EU/EEA’ (European Union/European Economic Area).
4.2 Development of the QRD template wording
This following section demonstrates the development of the QRD template wording from its first version
up to version 9 of March 2013.
4.2.1 QRD template section headings
All versions of the QRD template except versions 1 and 2 start with a contents list. The annotated QRD
template version 8 states that user testing has shown that an index is valued by patients, although user
testing research illustrates that package leaflets without one are not at a disadvantage49,52,53
.
In the Readability Guideline template and QRD template versions 3 to 9, the headings of sections 1, 3 and
4 use the same wording. In version 5, section 6 was included for using the heading ‘Further information’.
The heading of section 2 was altered in version 8 into ‘What you need to know before you <take> <use>
X’ and that of section 6 into ‘Contents of the pack and further information’, to provide the reader with
more details about the content to be expected in both sections (table 3).
24
Table 3: Development of template main section headings to be used in package leaflets
Template
version
Section 1 Section 2 Section 3 Section 4 Section 5 Section 6
Readability
Guideline36
,
QRD template
3 - 451
What X is
and what it
is used for
Before you
<take> <use> X How to
<take>
<use> X
Possible
side effects
Storing X
-
QRD template
5 - 6.151
Further
information QRD template
7.0 - 7.3.151
How to
store X
QRD template
849
and 948
What you need to
know before you
<take> <use> X
Contents of
the pack and
further
information
4.2.2 The information box
The first two versions of the QRD template provided no information box or index for the beginning of
package leaflets, but began with all active substances and excipients after the name of the medicine. From
version 3, an information box was present at the start of the package leaflet template which distinguished
between prescription only (Rx) and medicines available without prescription. The bracketing convention
means that the information can be adapted to the product requirements i.e. to reflect whether the medicine
is only administered by a doctor or bought by the patient. Strictly speaking, the brackets could also be
interpreted to mean that the entire box is optional which would cause a reduction of around one hundred
template words. The wording in the information box is the same in versions 3 to 6.1. Following some
changes, versions 7.0 to 7.3.1 were also identical. However, differences are seen in the information box
depending on whether a product is OTC or Rx. From version 8, a user who has been prescribed a medicine
is told to ask a doctor, pharmacist or nurse for more information, whereas the consumer of an OTC
preparation is only told to consult a pharmacist. The user of a prescription medicine is also told not pass it
on to others which is not required for OTC medicines. From version 8, the MAH is actively instructed not
to include this sentence for Rx products only used in a hospital setting. If an OTC product has been bought
the consumer is advised to consult a doctor if the condition does not improve after a certain number of
days.
25
Version 9 from 2013 includes a cross-reference to section 4 for the location of side effects although such a
cross reference to section 4 has been shown in results from readability testing not to be necessary66
.
Version 9 also introduces for the first time a black symbol (a black inverted equilateral triangle) for
medicinal products subject to additional monitoring for reasons of their specific safety profile which
includes new active substances, biological medicinal products, medicines given conditional approval, as
well as those listed by the Pharmacovigilance Risk Assessment Committee (PRAC)43
. This form of this
black symbol was described in the Commission Implementing Regulation (EU) No 198/291343
.
For OTC medicines, the statement that ‘This medicine is available without prescription’ is omitted from
version 8 for reasons which are not defined. The starting sentence and the advice to keep the leaflet are the
only sentences of the information box which are not found elsewhere in the QRD template versions 8 and
9. Reasons why these repeats are absolutely necessary are not provided in the advice contained in the
template. Table 4 presents the differences between template versions in the texts to be used after the name
of the medicine and active substances at the beginning of the package leaflet.
26
Table 4: Template texts to be used after the name of the medicine and active substances at the
beginning of the package leaflets for OTC medicines (changes in comparison to the predecessor are
highlighted in grey)
Template version
Readability.
Guideline
template*36
,
QRD template
3 - 451
QRD
template 5 -
6.151
QRD template 7.0 - 7.3.151
QRD template
849
QRD template
948
-------
---------
< This
medicine is
subject to
additional
monitoring. This
will allow quick
identification of
new safety
information. You
can help by
reporting any side
effects you may
get. See the end of
section 4 for how
to report side
effects.>
<Read all of this leaflet carefully because it contains important
information for you.
<Read all of this leaflet carefully
before you start <taking> <using>
this medicine because it contains
important information for you.
27
Template version
Readability.
Guideline
template*36
,
QRD template
3 - 451
QRD
template 5 -
6.151
QRD template 7.0 - 7.3.151
QRD template
849
QRD template
948
This medicine
is available
without
prescription, for
you to treat
mild illness
without a
doctor’s help.
Nevertheless
you still need to
use X carefully
to get the best
results from it.
This medicine
is available
without
prescription.
Nevertheless
you still need
to use X
carefully to
get the best
results from it.
This medicine is available
without prescription.
However, you still need to
<take> <use> X carefully to
get the best results from it.
Always <take> <use> this medicine
exactly as described in this leaflet or
as your <doctor> <,> <or> <pharma-
cist> <or nurse> <has> <have> told
you.
Keep this leaflet. You may need to read it again.
Ask your pharmacist if you need more information or advice.
You must see a doctor if your
symptoms worsen or do not
improve after {number of}
days.>
You must contact a doctor if
your symptoms worsen or do
not improve <after {number
of} days.>
If you get any
side effects,
talk to your
<doctor> <,>
<or> <pharma-
cist> <or
nurse>. This
includes any
possible side
effects not
listed in this
leaflet.
If you get any
side effects, talk
to your <doctor>
<,> <or>
<pharmacist> <or
nurse>. This
includes any
possible side
effects not listed
in this leaflet. See
section 4.
28
Template version
Readability.
Guideline
template*36
,
QRD template
3 - 451
QRD
template 5 -
6.151
QRD template 7.0 - 7.3.151
QRD template
849
QRD template
948
-------------------------------
If any of the side effects gets
serious, or if you notice any
side effect not listed in this
leaflet, please tell your
<doctor> <or>
<pharmacist>.>
You must talk to a doctor if you do
not feel better or if you feel worse
<after {number of} days>.>
*The pointed brackets are not found in the Readability Guideline template but are included in the QRD
template versions.
4.2.3 Section 1 of the QRD template
In the Readability Guideline template and QRD template versions 3 to 6.1, the name of the product, active
substances, list of excipients, name of the MAH and manufacturer were stated between the list of contents
and the start of section 1 of the package leaflet. In template versions 1 and 2, sections 1 to 5 dealt with this
information under clearly defined headings. The Readability Guideline from 199836
mentions that the
European Commission was aware that the leaflet would be more readable if this information was placed
towards the end of the leaflet, but due to the order stipulated in the current Directive 92/27/EEC25
it was
included at the predetermined position until the ruling could be modified. In QRD template version 7.0,
the aforementioned information was moved to section 6 due to the implementation of Directive
2004/27/EC24
, which altered the order of contents in the package leaflet.
Section 1 in template versions 3 to 7.3.1 has always been used to define the pharmacotherapeutic group
and type of activity of the active ingredient. This information is found in section 6 of template 1 and 2.
Explanatory text in subsequent versions of the template mentions that the therapeutic indications should be
stated in patient understandable language. From QRD template version 8 it is allowed that information on
the benefits of using the medicine can be included ‘as long as it is compatible with the SmPC, useful for
the patient and not of a promotional nature’49
.
In section 1, the QRD template from versions 3 to 7.3.1 only recommended one black printed sentence
which was for optional use only - ‘This medicine is for diagnostic use only.’ This was deleted in version 8
29
and the following was newly inserted ‘You must talk to a doctor if you do not feel better or if you feel
worse <after {number of} days.’ - a verbatim repetition of the last bullet point of the information box used
for OTC medicines49
. This sentence is retained in QRD template 9.
4.2.4 Section 2 of the QRD template
Section 2 is usually the largest in the package leaflet in terms of subheadings, and therefore the use of
carefully worded subheadings is crucial to aid the patient in finding relevant information.
Template versions 3 to 9 started with contraindications listed under ‘Do not <take> <use> X’ (table
5)48,49,51
. The statement under ‘Do not <take> <use> X’ informs patients not to use the medicine if an
allergy to one of the ingredients exist. Beginning with the wording ‘hypersensitivity (allergy)’ used in
version 3, this text was amended in version 7.0, and corrected from version 8 to ‘if you are allergic to
{active substance(s)} or any of the other ingredients of this medicine (listed in section 6)’48,49,51.
Warnings and precautions are provided under the next section 2 subheading which read up to version 7.3.1
‘Take special care with X’51
. This was changed from version 8 to the ‘Warnings and precautions’
subheading followed by the mandatory advice according to the template’s bracketing convention that
patients should contact healthcare professionals if listed aspects apply to them48,49
. Other additions from
QRD template version 8 are inclusion of alcohol in the food and drink subheading and the insertion of
fertility in the pregnancy and breast-feeding section if facts are known. The amended subheading ‘X
contains {name of excipient(s)}’ emphasises any excipients which need to be drawn to the user’s
attention48,49
.
30
Table 5: Subheadings (in bold) and standard statements (normal type) used in section 2 of the
template (changes in comparison to the predecessor are highlighted in grey)
Template version
Read-
ability
Guideline,
QRD
template 3
- 651
QRD
template 6.151
QRD template 7.0 - 7.3.151
QRD template 849
and 948
Do not <take> <use> X<:>
<if you are hypersensitive
(allergic) to {active
substance} or any of the
other ingredients of X>
<if you are allergic
(hypersensitive) to {active
substance(s)} or any of the
other ingredients of X.>
<if you are allergic to {active substance(s)}
or any of the other ingredients of this
medicine (listed in section 6).>
Take special care with X Warnings and precautions
<if you ….> Talk to your doctor <or> <pharmacist> <or
nurse> before <taking> <using> X
Children and <adolescents>
<Taking> <Using> other medicines Other medicines and X
<Please tell your <doctor>
<or> <pharmacist> if you are
taking or have recently taken
any other medicines,
including medicines obtained
without a prescription.>
<Tell your <doctor> <or> <pharmacist> if
you are <taking> <using>, have recently
<taken> <used> or might <take> <use>
any other medicines.>
<Taking> <Using> X with food and drink X with <food> <and> <,> <drink>
<and> <alcohol>
Pregnancy
Breast-feeding
Pregnancy and breast-
feeding
Pregnancy <and> <,> breast-feeding
<and fertility>
<Ask your doctor or pharmacist for advice before taking any
medicine.>
<If you are pregnant or breast-feeding, think
you may be pregnant or are planning to
have a baby, ask your <doctor> <or>
<pharmacist> for advice before taking this
medicine.>
31
Template version
Read-
ability
Guideline,
QRD
template 3
- 651
QRD
template 6.151
QRD template 7.0 - 7.3.151
QRD template 849
and 948
Driving and using machines
Important information about some of the ingredients of X <X contains {name the excipient(s)}>
<Taking> <Using> other
medicines*
<Please inform your doctor
or pharmacist if you are
taking or have recently taken
any other medicines, even
those not prescribed>
*Double use of ‘<Taking> <Using> other medicines’ in version 6.1 is probably a mistake in the template.
4.2.5 Section 3 of the QRD template
In QRD templates 1 and 2, section 8 was designated to contain the ‘Instructions for proper use’, while
from QRD template version 3 onwards and in the Readability Guideline template, package leaflet section
3 is for dosage instructions - advice on dosage, method and duration of use - followed by three subsections
relating to administration errors - overdose, missing a dose and stopping treatment36,48,49,51
.
Black printed subheadings have only been present since QRD template version 3 for the three
administration error sections. The subheading ‘Use in children’ has been part of the QRD template since
version 7.3.1 and was changed from QRD template version 8 to ‘Use in children and adolescents’48,49,51
.
General advice with almost identical wording has been provided in black ink for the start of section 3
since QRD template version 5 which informs patients to always use the medicine as the doctor has
instructed and to check with the doctor or pharmacist if they are unsure. From QRD template version 8
slightly different wording is provided to be used in the case of OTC medicines. Moreover, version 8
provides for the first time three black printed sentences for optional use relating to the divisibility of
tablets depending on the appearance of the score line.
The number of standard statements has greatly increased from version 3 to version 9. The influence of
Council Directive 2004/27/EC24
is reflected in versions of the template onwards from 7.0, which was
32
published in 2005. QRD template versions 2 to 6.1 and the Readability Guideline template also included
the optional sentence ‘<If you have the impression that the effect of X is too strong or too weak, talk to
your doctor or pharmacist.>’ which was deleted from version 7.0 onwards. The extra statement that
patients should consult their doctor or pharmacist in the case of further questions results from an addition
in Article 59 (d) which regulates the instructions for use of the product. The last sentence in this section
now reads ‘a specific recommendation to consult the doctor or the pharmacist, as appropriate, for any
clarification on the use of the product’.
4.2.6 Section 4 of the QRD template
Section 9 of QRD templates 1 and 2 contained the heading ‘Description of undesirable effects under
normal use’ and Directive 92/27/EEC instructed that the actions to be taken must be explained if side
effects should occur, including the communication of undesirable effects to the doctor or pharmacist,
especially if they are not mentioned in the package leaflet25
. This general advice has been printed in black
since QRD template version 3, including a second general sentence to be written at the beginning of
package leaflet section 4 that all medicines can cause side effects (table 6).
From QRD template 8, an optional subheading regarding children and adolescents is inserted providing
for the fact that additional side effects may occur which only affect this age group are found. It is only
since QRD template 8 that the patient has been advised to contact healthcare professionals if any side
effects occur. Previous template versions recommended that patients should contact an expert if the side
effect gets serious or is not listed in the package leaflet. This caused patients to understand that they
should not contact healthcare professionals in the case of a side effect which is listed in the package
leaflet53
.
QRD template 9 includes the new subheading ‘Reporting of side effects’, followed by a mandatory text
where the patient is actively encouraged to report any symptoms to different national contacts, when they
are believed to be side effects of using the medicine. This was brought about by the new
pharmacovigilance directives41,42
. Several examples of wording are provided by the template in the green
printed explanatory text and an additional Annex V gives the names and addresses of the national
authorities where side effects should be reported directly by the patient. This new wording has caused an
additional increase in the number of words by over 30 in the English template version.
33
Table 6: QRD template standard statements intended for use in package leaflet section 4 (changes in
comparison to the predecessor are highlighted in grey)
Template version
Readability
Guideline36
,
QRD template
3 - 6.151
QRD template 7.0 -
7.3.151
QRD template 849
QRD template 948
Like all
medicines, X
can have side
effects
Like all medicines, X can
cause side effects,
although not everybody
gets them.
Like all medicines, this medicine can cause side
effects, although not everybody gets them.
- - <Additional side effects in children <and
adolescents>>
If you notice
any side effects
not mentioned
in this leaflet,
please inform
your doctor or
pharmacist.
If any of the side effects
gets serious, or if you
notice any side effects not
listed in this leaflet,
please tell your <doctor>
<or> <pharmacist
If you get any side
effects, talk to your
<doctor> <or> <,>
<pharmacist> <or
nurse>. This
includes any possible
side effects not listed
in this leaflet.
Reporting of side effects
If you get any side effects, talk
to your <doctor> <or>
<,> <pharmacist> <or nurse>.
This includes any possible side
effects not listed in this leaflet.
You can also report any side
effects directly via the national
reporting system listed in
Appendix V. By reporting side
effects you can help provide
more information on the safety
of this medicine.
Apart from the changes in the black QRD template text, the green explanations which were provided in
this section in the annotated QRD template version 8, noted that serious side effects should be listed first
together with the most frequently occurring side effects. Clear handling instructions for the patient should
also be given in the case that serious side effects should occur. This should be followed by a list of other
side effects arranged according to descending frequencies. This method reflects advice contained in the
Readability Guideline36
. The green explanatory text in template version 9 was however changed to provide
the advice that the most serious side effects should be listed first followed by ‘a list of all other side
34
effects, listed by frequency and starting with the most frequent (without repeating the most serious and
most frequent included above)’48
. A frequency convention for side effects has also been recommended
since QRD template 8 (annotated version), where MedDRA system organ classes (SOC) should not be
used as the latter uses terms unfamiliar to patients38,67
.
4.2.7 Sections 5 and 6 of the QRD template
In the first two QRD templates, section 10 was designated for reference to the expiry date, storage
precautions and visible signs of deterioration. Since QRD template version 3 was developed, section 5 was
to be used for this storage information and instruction on keeping the medicine out of sight and reach of
children. Wording differs only very slightly between the Readability Guideline template and QRD
template versions 3 to 5. The advice to store medicines away from children was omitted in versions 6.0
and 6.1 for unnamed reasons and information relating to disposal of no longer required medicines has
been part of the QRD template since version 7.0. The statements contained in section 5 have undergone
slight changes mainly of an editorial nature since they were initially published. Standard storage
statements were originally included in the QRD template until version 6.0 when these were put into an
appendix.
Section 6 was originally not included in versions 3 to 5 of the QRD template as the information which is
now presented here had to be provided during the currency of these versions before the indication section
according to Directive 92/27/EEC25
. Versions 6.0 and 6.1 provided in the sixth section a list of local MAH
representatives and information relating to the last approval of the package leaflet. Up to date, this list has
always been optional but where one MAH representative address is presented, the addresses of all
EU/EEA countries must be included according QRD template versions 7.0 to 9.
The change in the information provided in section 6 caused by Directive 2004/27/EC was seen for the first
time in QRD template version 7.024
. Since this time, information relating to active substances, excipients,
description of the product, contents of the pack, the MAH and manufacturer must be provided at the end
of the package leaflet. The date of last approval was changed in version 8 to the last revision even though
this has been a requirement since Directive 2001/83/EC came into force39
. After this date, three standard
statements were included from QRD template version 7.0 onwards. The first should be used for medicines
approved under ‘conditional approval’ and states that more evidence is to come about the medicine, and
the second is for authorisations under ‘exceptional circumstances’ for example due to the rarity of the
disease. The third statement is intended for all centralised approved medicines and notes the EMA website
for more detailed information about the medicine. Subsequent to these three statements, information for
35
healthcare professionals can be presented since QRD template version 5 came into effect, however, this is
not compulsory.
4.3 Templates and related legal requirements in selected European and non-European countries
Templates for the package leaflet have been developed within and outside Europe due to relevant national
laws which govern the order and content of information, and therefore a thorough analysis of the legal
situation in countries where templates are used was considered to be an important stage in the project to
provide a comparison of what is considered important for patients by the authorities. On the basis of the
criteria described in section 3.2, Germany, the United Kingdom, New Zealand, Australia, Switzerland and
the United States were chosen for analysis of the legal requirements and guidelines which influence the
content of the package leaflet. Table 7 provides an overview of the internet sources which were found for
use in the analysis of the package leaflet and templates from selected European and non-European
countries. Although Germany and the United Kingdom are both in the European Union, where the QRD
template is applied, both countries were included, to examine country specific regulations and guidelines
which influence the content and appearance of the package leaflet in addition to the QRD template.
Table 7: Internet sources used to gain information on patient information, template structure and
content in selected countries
Country/Economic entity Internet sources
European Union - European Medicines Agency (EMA)58
- Heads of Medicines Agency (CMDh)68
- EUDRALEX69
Germany - Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)70
- German laws available on the internet71
United Kingdom - Medicines and Healthcare products Regulatory Agency (MHRA)72
- UK Legislation in internet73
Australia - Australian Government. Department of Health and Ageing,
Therapeutic Goods Administration74
- Commonwealth numbered regulations75
- Australian self-medication industry76
- Australian Government Common Law77
- Medicines Australia78
New Zealand - New Zealand legislation in internet79
- Medsafe website80
36
Country/Economic entity Internet sources
The United States of America - U.S. Food and Drug Administration (FDA)81
- U.S. Government Printing Office Federal Register82
- Justia U.S. Law83
Switzerland - Schweizerisches Heilmittelinstitut. Swissmedic84
- Schweizerisches Eigenossenschaft85
4.3.1 United Kingdom: Historical development and documents influencing the content of the
package leaflet
In the United Kingdom, some form of medicine regulation has existed since the time of King Henry VIII,
but it was in 1971 that a comprehensive regulatory system was first introduced86
. The package leaflet in
the UK is influenced by legally binding documents resulting from EU Directives and UK law as well as
non-legally binding guidance documents (table 8).
The Medicines act of 196887
was brought in force to govern the manufacture and supply of medicine87
and
subsequently the Misuse of Drugs Act was implemented in 197188
to control the use and supply of
narcotic drugs and psychotropic substances. Two executive agencies were responsible for overseeing and
enforcing the legislation: the Medicines Control Agency (MCA) and the Medical Devices Agency (MDA),
which in April 2003 merged to become the Medicines and Healthcare Products Regulatory Agency
(MHRA).
The Medicines Act 196887
controls manufacture, sale, supply and importation of medicinal products into
the UK. Three categories of medicine are defined: prescription only medicines which are only available
from a pharmacist, pharmacy medicines available only from a pharmacist but without a prescription, and
general sales list medicines which can be bought from any shop without a prescription.
The Medicines Act 196887
describes in section 86 that the appropriate ministers may make regulations
which impose the requirement of a package leaflet if they consider it necessary. The amendment in 1994
to the Medicines Act 196889
inserted a new subsection in section 86 that no medicinal product can be
supplied unless it contains a leaflet providing specific information. The content of the package leaflet in
the United Kingdom was regulated by the introduction of the Medicines (Leaflets) Regulations 197790
which set out in the attached schedule the ‘Particulars to be included in leaflets’ which included certain
European Community obligations under Council Directive 75/319/EC34
.
37
Table 8: Documents influencing the content of the package leaflet in the United Kingdom
Legally binding documents/regulations Non-legally binding documents
European Directives:
- Directive 2001/83/EC39
as amended by
Directive 2004/27/EC24
European specific guidance documents
- Guideline on the Readability of the label and
package leaflet of medicinal products for human
use38
- Guideline on the packaging information of
medicinal products for human use authorised by
the community91
- QRD human product information templates65
- Council of Europe. Standard Terms.
Pharmaceutical dosage forms, routes of
administration, containers. 5th Edition92
- EMA Quality review of Documents: Reference
documents and guidelines93
- Volume 3b Guidelines. Excipients in the label and
package leaflet of medicinal products for human
use (July 2003)94
UK laws:
- Medicines Act 196887
- The Medicines Act 1968 (Amendment) (No.2)
Regulations 199489
- The Medicines (Leaflets) Regulations 197790
- The Medicines (Leaflets) Amendment
Regulations 199295
- The Medicines for Human use (Marketing
Authorisations Etc.) Regulations 199496
- The Medicines for Human Use (Marketing
Authorisation Etc.) Amendment Regulations
199897
- The Medicines (Codification Amendments Etc.)
Regulations 200298
- The Medicines for Human Use (Marketing
Authorisations Etc.) Amendment Regulations
200399
UK specific guidance documents
- MHRA. Guidance on patient information leaflets.
Always read the leaflet101
- MHRA. Glossary of Medical Terms in Lay
Language102
- MHRA. Can you read the leaflet? A guideline on
the usability of the patient information leaflet for
medicinal products for human use103
- MHRA. Signposting from the patient information
leaflet to additional sources of information and
other services104
- MHRA. Guidance on communication of risk in
patient information leaflets105
- MHRA. Further guidance on designing patient
information leaflets and how to achieve success
in user testing106
38
Legally binding documents/regulations Non-legally binding documents
- The Medicines (Marketing Authorisations and
Miscellaneous Amendments) Regulations
2004100
The Amendment to the Medicines (Leaflets) Regulations in 199295
implemented in part Council Directive
92/27/EC25
. The regulations defined that the leaflet should be drawn up in accordance with the summary
of product characteristics, described additional requirements for form and the content of the leaflet and
imposed special requirements for the leaflets of radiopharmaceuticals. The Medicines for Human use
(Marketing Authorisations Etc.) Regulations 199496
fully implemented the requirement for detailed
information to accompany medicines into UK legislation. The Medicines for Human Use (Marketing
Authorisation Etc.) Amendment Regulations 199897
and 200399
specified new necessary warnings for the
package leaflets for selected active ingredients. The Medicines (Codification Amendments Etc.)
Regulations 200298
served to amend the Medicines Act 196887
and fully applied European Council
Directive 2001/83/EC39
to UK legislation. The Medicines (Marketing Authorisations and Miscellaneous
Amendments) Regulations 2004100
implemented Directive 2004/27/EC24
of the European Parliament and
of the council into UK Drug Law. The explanatory note in this amendment specifically mentions the
provisions now required that the package leaflet ‘must reflect the results of consultations with target
patient group’ to comply with Article 59 (1) of the Council Directive 2001/83/EC39
. When the amendment
came into force on January 1st 2005 in the UK it became a legal requirement for every product with a
marketing authorisation on this date, that all marketing authorisation holders submit applications to update
marketing authorisations with an approved patient information leaflet by July 1st 2008
100.
The Patient Information Quality Unit which is part of the Vigilance and Risk Management of Medicines
Division of the MHRA is responsible for approving these patient information leaflets. The MHRA
provides numerous guidance documents on its webpage to aid the marketing authorisation holder in
writing the patient information leaflet. The use of these numerous guidance documents, which are not
legally binding, maintains an element of flexibility which is not the case with the formal legal directives.
No template for the package leaflet other than that in the Readability Guideline 199836
or the QRD
template has been developed or used in the United Kingdom.
4.3.2 4.3.2 Germany: Historical development and documents influencing the content of the package
leaflet
Due to regulations to create a united Europe, the Federal Ministry of Health was founded in Germany in
1961. The German Drug Law (AMG) of 1976107
, which came into force on January 1st 1978, made the
39
inclusion of a package leaflet compulsory and defined which information should be contained within this
document108
. In a second amendment of this ruling in 1986, the readability of the package leaflet was
already starting to be considered: before the list of required information, an additional statement was
included stating that the information should be ‘allgemeinverständich’32
(generally comprehensible). The
role of the summary of product characteristics for medical professionals was also more clearly defined. In
1994, the fifth amendment to German Drug law was used to implement European Council Directive
92/27/EEC25
while the 14th amendment in 2005 put Directive 2004/27/EC
24 into practice. This 14
th
amendment enforced major structural changes in the contents of the package leaflet and made user-testing
a requirement for medicines receiving marketing authorisation after September 2005109
.
It is not only European Guidelines and German Drug Law which directly influence the contents of the
package leaflet in Germany, but also several other legally binding documents. The ‘Arzneimittel-
Warnhinweisverordnung’110
(regulation for warning notices on medicines) determines warnings to be
included on the immediate inner packaging, outer packet and in the package leaflet for products containing
ethanol and tartrazine. ‘Verordnung über die Angabe von Arzneimittelbestandteilen’111
(regulation for
declaration of certain components in medicines) clarifies how certain buffers, colourings, preservatives,
aromas and odorants should be declared while the ‘Bezeichnungsverordnung’112
(denotation regulation)
defines the names of ingredients and excipients used in medicinal products.
The ‘Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM))’ (Federal Institute for Drugs and
Medical Devices) is the responsible authority for approving the patient information leaflets supplied with a
medicine in Germany. BfArM additionally publishes numerous documents which should be used by the
marketing authorisation holder for the product information such as ‘Mustertexte’59
(sample texts)
contained in a data base for many commonly used active ingredients and the ‘Besonderheitenliste des
BfArM’113
which is based on the Excipients Guideline published by the European Commission94
. However
the sample texts are going to be replaced by ‘Referenztexte’ (reference texts) which are basically the
Summary of Product Characteristics and package leaflet from the medicine originator114
.
The introduction of strengthened ruling regarding doping has also influenced the package leaflet in
Germany. The ‘Gesetz zur Verbesserung der Bekämpfung des Dopings im Sport (Anti-Doping Gesetz)’115
(law to improve the fight against doping in sports) which came into force in November 2007 made
inclusion of a warning statement relating to the type of substance contained in the product mandatory -
some doping substances can cause severe danger to health. The appendix contained in the
‘Übereinkommen vom 16. November 1989 gegen Doping’116
(convention against doping from November
16th 1989) provides a list of prohibited substances. The World Anti-Doping Agency (WADA) publishes an
40
international standard of prohibited substances annually117
. Table 9 summarises the documents influencing
the package leaflet in Germany.
Table 9: Documents influencing the contents of the package leaflet in Germany
Legally binding documents/regulations Non-legally binding documents
European Directives:
- Directive 2001/83/EC39
as amended by Directive
2004/27/EC24
European specific guidance documents:
as listed in table 8
German laws:
- ‘Anti-Doping Gesetz’115
(Anti-doping Law)
- ‘Arzneimittelgesetz’107
(German Drug Law)
- ‘Arzneimittel-Warnhinweisverordnung’110
(Regulation for warnings notices on medicines)
- ‘Verordnung über die Angabe von
Arzneimittelbestandteilen’111
(Regulation for
declaration of certain components in medicines)
- ‘Bezeichnungsverordnung’112
(Regulation regarding
the names of ingredients for medicinal products)
Germany specific guidance documents:
- Recommendations from BfArM for the
presentation of package leaflets118
- ‘Wortlaut der für die Packungsbeilage
vorgesehenen Angaben (kommentierte Fassung,
Januar 2007)’119
(commented template for a
package leaflet from BfArM)
- ‘BfArM Beschreibung der Häufigkeiten von
Nebenwirkungen’120
(BfArM description of the
frequency of side effects)
- ‘BfArM Mustertexte’59
(sample texts)
- ‘Besonderheitenliste des BfArMs’113
(excipients
list)
The first template for use for package leaflets with headings, standard statements and explanatory notes
was initially produced in Germany in 199330
. The document was named ‘Anleitung zur Erstellung einer
Gebrauchsinformation’ (Guidance for the preparation of a package leaflet) and was prepared according to
European Directive 92/27/EEC25
. The main purpose of the guideline was to provide for a package leaflet
which conformed to the legal regulations with patient suitable wording. This guidance document was
published a year later in 1994 by the BfArM as the ‘Erste Empfehlung zur Gestaltung von
Packungsbeilagen’121
(first recommendations for the design of package leaflets). The content and order of
information was as required by German Drug Law which reflected European ruling at the time. This
guideline was updated in 2002122
and included recommendations on how to design the leaflet and make it
more user friendly which were provided on the basis of a translation of the model leaflet and advice
contained in the first Readability Guideline36
. A distinction was also made in the guidance document
between prescription only and OTC medicines and it included a general introductory text at the start of the
41
leaflet similar to today’s versions of the QRD template. This template was again updated in 2007 by the
BfArM and published on their website119
.
4.3.3 Legal requirements and guidelines influencing the content of the package leaflet in
Switzerland
At the beginning of the last century, control of pharmaceuticals was regulated by the individual cantons in
Switzerland123
. In 1934, a central office was set up in Bern known as the ‘Interkantonale Kontrollstelle
(IKS)’ (Intercantonal Board of Control) which assessed medicines, and carried out laboratory
investigations, as well as being an information point for authorities, doctors and pharmacists. Swissmedic,
which began its operations in 2002, took over from the IKS. It is currently the competent authority in
Switzerland responsible for authorising, licensing and supervising therapeutic products.
The ‘Bundesgesetz über Arzneimittel und Medizinprodukte (Heilmittelgesetz)’124
(Swiss Drug Law), which
came into force in 2002, regulates the marketing authorisation and distribution of pharmaceuticals in
Switzerland. In addition, the ‘Verordnung des Schweizerischen Heilmittelinstituts über die Anforderungen
an die Zulassung von Arzneimitteln (Arzneimittel-Zulassungsverordnung- AMZV)’125
(Regulation for the
approval of marketing authorisation for pharmaceuticals) and the ‘Verordnung über die Arzneimittel
(Arzneimittelverordnung, VAM)’126
(Pharmaceuticals regulation) provide additional rulings based on the
Swiss Drug Law). The Pharmaceuticals regulation defines five distribution categories - A to E - for
pharmaceutical products in Articles 23 - 27. Categories A and B are for prescription only medicines,
categories C and D are for medicines available without prescription but where expert advice is needed, for
example from a pharmacist, and E is for medicines which can be bought over-the-counter without any
specialist guidance.
Inclusion of a package leaflet has been mandatory since Swiss Drug Law124
came into force. This patient
information must be published in the three official languages i.e. German, French and Italian and
according to Article 16 of this law, should continually be updated according to current scientific
knowledge125,126
. In 2004, Swissmedic introduced the regulation that the patient information had to be
published electronically127
.
The AMZV125
stipulates in Article 14 in connection with appendix 5.1 the order of sections which must be
contained in the patient information and their content in the form of heading titles and fixed statements.
Different mandatory statements must be included for prescription and OTC medicines. Products
containing alcohol must include an extra warning in the package leaflet regarding the percent of alcohol,
and this is detailed in appendix 2 of the AMZV125
. The European Excipients Guideline is not applicable
42
for use in Switzerland and declaration of certain specific excipients is defined in appendix 3 of the
AMZV125
. Here preservatives, antioxidants, colourings, sweeteners and flavour enhancers are named
which must be stated on the container, outer packet and in the information on the medicinal product.
Products to be used cutaneously, on mucous membranes or the eyes must also declare lanolin and its
derivatives, lauryl sulfate and its salts, macrogols up to a molecular mass of 900 and propylene glycol.
The requirements for the patient information of homeopathic or anthroposophic medicines, traditional
herbal medicinal products and Asiatic drugs are defined in appendices 5.2, 5.3 and 5.4 respectively in the
AMZV125
. Here extra fixed statements appropriate for the type of product are included. The legally
binding and guidance documents influencing the content of the information in the package leaflet in
Switzerland are summarised in table 10.
Table 10: Documents influencing the content of the package leaflet in Switzerland
Legally binding documents/regulations Non-legally binding documents
- ‘Bundesgesetz über Arzneimittel und
Medizinprodukte (Heilmittelgesetz)’124
(Drug law)
- ‘Verordnung des Schweizerischen
Heilmittelinstituts über die Anforderungen an die
Zulassung von Arzneimitteln (AMZV)’125
(Regulation for the approval of marketing
authorisation for pharmaceuticals)
- ‘Verordnung über die Arzneimittel
(Arzneimittelverordnung, VAM)’126
(Pharmaceuticals regulation)
- ‘Mustertexte für rezeptpflichtige NSAR.
Patienteninformation (Abgabekategorie B)’128
(Sample text for prescription only NSAR. Patient
information)
- ‘Merkblatt: Erläuterung zur
Patienteninformation’129
(Information
sheet: explanations for patient
information)
In Switzerland, the ‘Merkblatt: Erläuterung zur Patienteninformation’129
(Information sheet: explanations
for patient information) is published by Swissmedic. This document can be considered as a template as the
headings are given as required in the relevant legislation (AMZV125
), with additional information on how
best to fill in the section. The first version of this information sheet was made available in August 2010130
and was developed according to appendix 5.1 of AMZV125
and a connected publication in the Swiss
Medical Journal from 2002131
. The guidelines which were implemented in the information sheet were
43
already part of Swiss legislation which had been in force since 2001. Since 2010, the information sheet
has been revised four times for editorial modifications or to take current legal requirements into account.
The most recent information sheet was published in November 2011129
. Four different templates are
provided in the information sheet for prescription and OTC medicines which are either classed as ‘normal’
medicines, homeopathic and anthroposophic medicines, traditional herbal medicines and Asiatic drugs
without an indication. Many of the statutory statements, which are often over 20 words in length, from the
AMZV125
are identical for all four classes of medicine although product specific sentences are also
included. In a similar manner to the Readability Guideline, it is suggested that foreign words and specialist
terms should be avoided and where their use is unavoidable, they should be explained.
In a similar fashion to the German sample texts published by BfArM59
, Swissmedic published sample
texts in 2010 for prescription only NSAR (non steroidal antirheumatics) and NSAR intended for self-
medication128,132
. Two versions of each text were published - one for health professionals and the other for
patients. Whereas the German sample texts provide a complete text where the marketing authorisation
holder need only insert their own product name, the Swiss version is less extensive, especially for
prescription only NSAR128
- here, only the text which is mandatory for the patient information is listed.
The text version for NSAR for self-medication132
has a more similar format to the German texts where
almost the complete content of each section is described with gaps left in the headings for insertion of the
product name.
4.3.4 Regulations and history of patient information and the development of Consumer Medicine
Information (CMI) in Australia
Medicines in Australia are classified into three categories: registered medicines (prescription and non-
prescription), listed medicines (most over-the-counter medicines) and complementary medicines (vitamin,
mineral, herbal, aromatherapy and homeopathic products). Before a drug can be brought onto the market
in Australia, it must be evaluated by the Therapeutic Goods Administration (TGA). This is the regulatory
authority of the Australian Government Department of Health and Ageing for therapeutic goods133
. The
TGA is responsible for ensuring that therapeutic goods (medicines and medicinal devices) are safe and
suitable for their intended purpose. The Therapeutic Goods Act was first introduced in Australia in 1989134
and had the objective of maintaining a national system of controls relating to the quality, safety, efficacy
and timely availability of therapeutic goods either used in or exported from Australia134
. This act was
amended in 1991 following the release of a report by Professor Peter Baume135
which also resulted in the
same year in a reorganisation of the functions of the TGA. The Baume report was commissioned by the
Minister for Aged, Family and Health Services to conduct an inquiry into the access to drugs and the
reform of the drug evaluation process in Australia136
. Following the release of the 232-page report, the
44
Government announced that Professor Baume’s recommendations would be adopted as a package. Before
the Baume Report, nearly all applications for prescription medicines were reviewed by the Australian
Drug Evaluation Committee (ADEC)137
. The Baume Report was commissioned due to the perceived
dissatisfaction with this drug evaluation system, the main criticism involving the timely availability of
drugs. The TGA did not meet its own performance targets, the ADEC process itself was a source of delay
and there were holdups in the approval process following meetings of the ADEC. The recommendations
of the Baume Report aimed to improve the evaluation process for prescription drugs while still
maintaining public protection137
. The amendment to the Therapeutic Goods Act 1989 therefore included
time limits for the completion of evaluations of applications of certain drugs.
In response to lobbying by consumer groups who called for improvements in the way that medicines were
prescribed, dispensed and used, the Commonwealth Government established two advisory groups around
the same time; the Pharmaceutical Health and Rational use of Medicines (PHARM) Working Party and
the Australian Pharmaceutical Advisory Council (APAC)138
. The PHARM went on to formulate the
Quality Use of Medicines (QUM) policy in 1992 which encompassed a partnership between government,
industry, consumers and health professionals.
The Baume Report 1991 recommended that a patient information document be developed for all
prescription medicines135
. These patient information documents were originally known as Consumer
Product Information Leaflets, but this was later changed to Consumer Medicine Information (CMI) to
reflect the fact that the document was intended to provide the user with information about a medicine139
.
This was one of the first achievements of the new partnership under the QUM, that consumers worked
with the government and pharmaceutical industry to produce these leaflets138
. The term Consumer
Medicine Information (CMI) was first utilised in New Zealand and then adopted in Australia140
. CMIs
became mandatory for all new prescription medicines from January 1st 1993, and in January 1
st 2003 was
extended to cover all prescription medicines as regulated by the Therapeutic Goods Regulation act134
. The
requirement for a CMI for pharmacist-only medicines was decided in July 1995 and, as of January 1st
2004, all pharmacist-only medicines were obliged to have a CMI. Schedules 12 and 13 of the Therapeutic
Goods Regulations act define the content of the patient information document for prescription and non-
prescription medicines respectively134
. The requirements stipulated by Australian law are very similar to
those laid down in the European Directive 2001/83/EEC, although the information does not need to appear
in the order outlined in the regulation, contrary to Article 59 in the European Union which determines the
order. Australian CMIs must also include the expected effect of using the medicinal product and whether
its use has habit forming potential, neither of which is reflected in Article 59. However, since publication
45
of QRD template version 8, the template allows information to be included on the benefits of using the
medicine.
Each medicine, whether prescription or pharmacist-only, must also have a Product Information (PI)
intended for use by health professionals. Both PI and CMI are written by the pharmaceutical company
responsible for the medicine and are subsequently approved by the TGA. The contents of the PI are
similar to the European SmPC and include amongst others the name of the medicine, description,
pharmacology, clinical trials, indications, precautions, adverse effects, dosage and overdosage. All CMIs
must be consistent with the PI but there is no legal requirement that all information contained in the PI
must be contained in the CMI140
.
Most CMIs are leaflets contained in the package as an insert while others are available on an electronic
database which can be accessed by pharmacists, or as a leaflet which the pharmacist can give to the
consumer. In 1995, the CMI content/Quality Assurance Reference Group was established to assess CMIs
and provide advice on their development141
. Core CMIs are available for a large range of active
ingredients such as ACE inhibitors, diuretics, numerous antibiotics and NSAIDs. The first core CMIs for
prescription medicines became available in 1993. Most similar to the European QRD template is the
general core CMI for Product X which was first finalised in March 2001142
. The current version published
in August 2005 can be downloaded from the Medicines Australia webpage143
. In addition to the required
sections, which are described in the Therapeutic Goods Regulations134
, the CMI includes a selection of
standard statements under each section heading and advice on how best to present information. Table 11
provides a summary of legally binding documents and guidelines influencing the package leaflet in
Australia.
Table 11: Documents influencing package leaflets in Australia
Legally binding documents/regulations Non-legally binding documents
- Therapeutic Goods Regulations 1990134
(Schedule 12 for prescription medicines and
Schedule 13 for pharmacist only).
- Standard for the Uniform Scheduling of
Medicines and Poisons (SUSMP)144
.
- TGA Approved Terminology for Medicines145
.
- Core CMIs available from Medicines Australia143
.
- Writing about medicines for people 3rd
Edition146
- Vocabulary for consumer medical information
(CMI) available from Medicines Australia147
.
46
4.3.5 Regulations and history of patient information and Consumer Medicine Information (CMI)
in New Zealand
In New Zealand, the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) is
responsible for regulating products for therapeutic purpose which includes medicines, herbal remedies and
medical devices. The Medicines Act 1981148
and the Medicines Regulations 1984149
are administered by
Medsafe. The Medicines Act 1981148
controls the manufacture and distribution of medicines and related
products, the conduct of clinical trials and the advertising and sale of medicines, while the Medicines
Regulations 1984149
specify amongst others, the requirements for advertisements, licences, data sheets,
labelling and packaging of medicines and related products. The Medicines Act 1981148
established a
classification system for prescription only medicines, restricted medicines or pharmacy only medicines,
while the Medicines Regulations 1984149
lists the medicines in these categories in Schedule 1 parts 1 to 3
respectively.
There is no legal requirement for pharmaceutical companies in New Zealand to produce patient
information leaflets, although if the required information stipulated in Regulation 13 of the Medicines
Regulations 1984149
for the labelling of the product cannot be present on the container of the medicine, for
example, if the container is too small, a separate information sheet must be provided for the patient.
Instructions for dosage, indication and ingredients are described on the container but contraindications,
side effects or interactions with other medicines are not mentioned. However, consumers in New Zealand
can, in addition to advice provided by their doctor, refer to the Consumer Medicine Information (CMI)
which is very similar to that seen in Australia. For a great number of active ingredients, CMIs can be
accessed on the Medsafe website and were introduced in New Zealand from around 1998150
. The
pharmaceutical companies are responsible for producing the CMI which contains detailed advice on how
to use the medicine, side effects etc. Though there is no legal requirement for a CMI to be produced for
each product, where a CMI is present it must be prepared using the guidelines set by Medsafe which are
contained in Part 10 of the Guideline on the Regulation of Therapeutic Products in New Zealand151
. This
guideline was developed in collaboration with doctors, pharmacists and consumers. Part 10.4 contains the
‘Template for preparing CMI for New Zealand Consumers’152
. The template for preparing CMI is for both
prescription and non-prescription drugs and makes no distinction between the two categories, neither for
headings nor standard statements which are present. Brief advice is included on what information should
be included under each section heading.
Pharmaceutical companies are required to prepare data sheets for all prescription and pharmacist-only
medicines in accordance with the Medicines Regulations 1984149
and Medsafe regulatory guidelines.
General sales medicines are not required to have a data sheet. The data sheets greatly resemble the
47
European Union SmPC and can be viewed on the Medsafe website. Table 12 provides a summary of
documents and guidelines influencing the package leaflet in New Zealand.
Table 12: Documents influencing package leaflets in New Zealand
Legally binding documents/regulations Non-legally binding documents
- No legal requirements to produce patient
information leaflets
- Guideline on the Regulation of Therapeutic
Products in New Zealand151
- Template for preparing CMI for New Zealand
Consumers’152
4.3.6 Regulations and history of patient information and templates in the United States
Written consumer information takes three main forms in the United States for prescription medicines, and
includes the patient package insert (PPI), medication guides (usually called MedGuides) and consumer
medication information (CMI)153
. Over-the-counter medicines are not required to contain a package leaflet
but must abide by the drug labelling ruling described later154
. The situation for prescription only medicines
is summarised in table 13.
Table 13: Summary of consumer information for prescription medications in the United States
Consumer medication
information (CMI)
Medication guide Patient package insert
(PPI)
Availability Dispensed voluntarily
by the chemist
Must be dispensed by the
chemist
Contained in the packet
For which
medicines?
All new prescription
medicines
Prescription medicines
which the FDA decides
have a serious and
significant health concern
Oral contraceptives and
estrogen containing
products. FDA or drug
companies can decide on
additional PPIs
Who writes it? Organisations other than
the drug’s manufacturer
Drug company Drug company
Is it FDA
approved?
No Yes Yes
The Food and Drug Administration (FDA) is the agency within the US Department of Health and Human
Sciences responsible for protecting public health with respect to safety and effectiveness of drugs,
48
vaccines, medical devices and cosmetics to name but a few. Its origins can be traced back to around 1848
although it was not known under its present name until 1930155
. The code of federal regulations is the
codification of general and permanent rules published in the federal register by the executive departments
of the United States government. Title 21 is the portion of this legislation which governs food and drugs.
Proposed rules in the United States are first published for public comments which are then analysed
resulting if necessary in the rule being modified, before the final rule is published in the federal register
and subsequently incorporated into the next edition of the code of federal regulations.
The development of mandatory patient information in the United States began in 1968 when federal
regulations demanded that a warning was included on the packaging of isoproterenol inhalation
medication that excessive use can cause breathing difficulties156
. However, this advice could be included
on the immediate container label or in the form of a printed statement in the package. This was followed in
1970 by the requirement from the FDA that patient information should be dispensed with (either in the
packet or as an accompanying document issued to the patient) oral contraceptives157
and in 1977 for
estrogens158
. The relevant legislation defined that the patient package insert should detail risk and benefits
of birth control pills. In the 1970s the FDA began evaluating the usefulness of patient labelling for
prescription drugs, which resulted in a number of regulatory steps to ensure the availability of written
consumer information159
. Regulations were proposed in 1979 that would require manufacturers or
distributors to prepare written PPIs for prescription drug products generally, and these were to be
distributed by the persons dispensing the medication160
. The PPI was to contain a summary of information
about the product and detail on how it should be used, as well as information on side effects, precautions
and interactions. In 1980, a final regulation establishing requirements and procedures for the preparation
and distribution of PPIs was published and in the same year, the FDA provided draft guideline PPIs for ten
widely used prescription drugs or drug classes such as benzodiazepines and thiazide160
. In 1982, the FDA
revoked these regulations, partially due to assurances from the private sector and pharmaceutical
companies who felt that the goals of this final rule could be met more successfully without the restrictions
of a regulation159
. To coordinate these efforts, the voluntary organisation known as the National Council
on Patient Information and Education (NCPIE) was formed.
A survey of estimated distribution rates carried out by the FDA however revealed that significant numbers
of patients still did not receive information with their medications and in 1995 the FDA was compelled to
propose the ‘Prescription Drug Product Labeling; Medication Guide Requirements’160
in order to improve
the quality and distribution of patient information. The FDA stated in this planned ruling that ‘Inadequate
access to appropriate patient information is a major cause of inappropriate use of prescription
medications, resulting in serious personal injury and related costs to the health care system’160
and
49
therefore specific time frames and goals were laid down to ensure that by the year 2006, 95 percent of
people receiving new prescriptions would receive useful written information. The ruling also required
manufacturers to prepare FDA approved medication guides for specific prescription products which the
FDA had determined to have serious and significant public health concerns.
However, calls from the private sector resulted in the congress enacting the public law 104 - 180161
whereby the FDA was prohibited from taking regulatory steps to specify a uniform content or format for
written information. However, the goals and timeframes from the FDA proposed 1995 ruling were
adopted but the main responsibility of improving performance was moved to the private sector. Enacting
of public law 104 - 180 also resulted in a Steering Committee being created which developed the ‘Action
Plan for the Provision of useful Prescription Medicine Information’. This action plan described criteria to
evaluate whether a particular piece of written medication information is useful to consumers162
.
The final ruling on medication guide requirements for prescription drugs was published by the FDA in
1998163
which described the content of such a guide. The guides prepared by the manufacturer are
approved by the FDA and are required to be distributed with each prescription medicine. The Food and
Drug Administration Amendments Act of 2007164
created a new section 505 which is used by the FDA to
implement a tight timeframe for the development of a medication guide and changes to labelling based on
new safety-related information.
In December 2000, the FDA proposed to amend its regulations governing the format and content of
labelling for human prescription drug products165
. However, it took some years for the major revision to
the initial guidelines for this labelling to be enforced in 2006 in the Code of Federal Regulations Title
21166
. The newly designed leaflet enclosed in the package was to provide healthcare practitioners with the
most up-to-date information in an easy-to-read format to draw attention to the most important pieces of
information167
. Any FDA approved patient labelling must be reprinted or accompany the labelling. The
most significant changes were inclusion of a box called ‘Highlights’ which summarised the most
important information and a table of contents for easy reference. The FDA issued four guidance
documents in 2006 in coordination with the publication of the final rules, which are not legally
enforceable but should be viewed as recommendations. These papers described the adverse reactions
168and clinical studies section
169 as well as the warnings and precautions, contraindications and boxed
warnings section (draft)170
. The fourth guidance document, which was a draft, provided information on
how the new content and format requirements should be implemented171
. Sample package leaflets for four
fictitious drugs were also published by the FDA to demonstrate the new format. In 2009 a fifth draft paper
was released on the clinical pharmacology section172
, and in 2010 a guidance document followed on the
50
dosage and administration section173
. Table 15 provides a summary of legally binding documents and
guidelines influencing consumer information on medicines in the United States.
Table 14: Documents influencing consumer information on medicines in the United States
Legally binding documents/regulations Non-legally binding documents
Leaflet for prescription medicines for healthcare
practitioners:
- Code of Federal Regulations Title 21, Part 201
Labeling Requirements for Prescription Drugs
and/or Insulin166
.
Medication Guides:
- Code of Federal Regulations Title 21, Part 208;
Medication Guides for Prescription Drug
Products163
.
- Food and Drug Administration Amendments
Act (2007)164
OTC Medicines:
- Code of Federal Regulations Title 21, Part 201
Labeling Requirements for Over-the-Counter
Drugs 154
Package leaflet for prescription medicines:
Guidance for Industry documents from U.S.
Department of Health and Human Services, Food
and Drug Administration, Center for Drug
Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER):
- Clinical Studies Section of Labeling for Human
Prescription Drug and Biological Products -
Content and Format169
.
- Adverse Reactions Section of Labeling for
Human Prescription Drug and Biological
Products - Content and Format168
.
- Warnings and Precautions, Contraindications
and Boxed Warnings Section (draft)170
.
- Implementing the New Content and Format
Requirements171
- Clinical Pharmacology Section172
- Dosage and Administration Section173
- U.S. Department of Health and Human
Services; Food and Drug Administration;
Center for Drug Evaluation and Research
(CDER); Center for Biologics Evaluation and
Research (CBER); Center for Veterinary
Medicine (CVM); Center for Devices and
Radiological Health (CDRH). Guidance for
Industry. Presenting Risk Information in
Prescription Drug and Medical Device
Promotion (Draft)174
51
Legally binding documents/regulations Non-legally binding documents
Consumer Medication Information:
- Useful Written Consumer Medication
Information (CMI)159
OTC medicines:
- U.S. Department of Health and Human
Services; Food and Drug Administration;
Center for Drug Evaluation and Research
(CDER). Guidance for Industry. Labeling OTC
Human Drug Products Using a Column
Format175
- U.S. Department of Health and Human
Services; Food and Drug Administration;
Center for Drug Evaluation and Research
(CDER). Guidance for Industry. Labeling OTC
Human Drug Products - Questions and
Answers176
4.4 Comparison of QRD template version 9 to non-EU package leaflet templates
4.4.1 Comparison of QRD template version 9 to the Swiss package leaflet template
Although the Swiss package leaflet must be printed in the three main official languages spoken in
Switzerland, the template is only provided in German, in contrast to the QRD template version 9 which is
published in the languages of every country where it is intended to be used. Table 15 shows the contents
of the Swiss template in comparison to QRD template 9. Although the QRD template 9 contains fewer
headings than the Swiss template, the actual order of the information contained is very similar.
The Swiss package leaflet template starts with a fixed text information box that distinguishes between
prescription and non-prescription medicines with similar wording to that of the QRD template 9.
Additionally the terms ‘Drogerie/Drogistin’ (drug store/druggist) are regularly included for non-
prescription medicines of the category D which can be sold in drugstores in Switzerland. These are
specialist shops which sell cereals, health foods, cosmetics and wellness products. Although the headings
are numbered, the Swiss patient information contains no list of contents in contrast to the QRD template 9.
Subheadings are not suggested in any section in Switzerland. The order of section 1 and 2 of the Swiss
template can be swapped on request by the marketing authorisation holder and not all sections which are
described in Article 14 of the AMZV125
are mandatory. Section 4 ‘Was sollte dazu beachtet werden?’
52
(What should be taken into consideration?) is not obligatory in Switzerland and should only be included
when necessary or useful to deliver information to the patient in addition to that regarding the medical
treatment. Here is meant dietary measures, general codes of behaviour such as using mosquito repellents
in addition to malarial drugs and influence of the medicine on urine, stool or contact lenses. However, this
section must be included when a relevant warning is required for diabetics describing the bread units
contained in the product. Addition of such ‘behavioural’ information is not provided in the QRD template
9 although bread units may be included where relevant.
In the Swiss template, instructions on what to do in the event of an overdose, in the case of a forgotten
dose, or abruptly discontinuing treatment, must only be included if they are considered necessary and
meaningful. The section for pregnancy and breast feeding can also be omitted in Switzerland, for example
with products specifically for use in children or only in men. Although the brackets in the QRD template 9
mean that exclusion of the three sections - overdose, forgotten dose or stopping treatment - is possible,
omission of the section on pregnancy and breast-feeding is not allowed. In Switzerland, section 15
‘Herstellerin’ (manufacturer) is also not obligatory as in the QRD template 9.
Compulsory statements for alcohol and azo dye containing products are present in the Swiss template as
regulated by the AMZV125
. Warnings for these ingredients are regulated in the European Commission’s
Excipients Guideline94
rather than a directive. In section 6 ‘Wann ist bei der Einnahme/Anwendung von …
Vorsicht geboten?’ (When should care be taken during use of …?) patients who are allergic to azo dyes,
acetylsalicylic acid and prostaglandin inhibitors are warned not to take the product. A fixed statement
describing the side effects which can be caused by azo dyes is also mandatory in section 9. For alcohol
containing products, sections 6, 10 and 11 of Swiss package leaflets must all include relevant statements
as specified in appendix 2 of the AMZV125
.
53
Table 15: Main headings to be used in the Swiss package leaflet template for prescription and OTC medicines from AMZV in comparison to headings
(bold type) and subheadings (normal print) from QRD template 9
Swiss template125
QRD template 948
Section
number
Section heading Section
number
Section heading/Subheading
1 Information für Patientinnen und Patienten* (Information for
patients)
{(Invented) name strength pharmaceutical form}
{Active substance(s)}
Information box prescription/OTC medicines and index ‘What is
in this leaflet’
2 (a) Name des Präparates* (Name of the product)
3 Was ist … und wann wird es angewendet? (What is …. and
what it is used for)
1 What X is and what it is used for
4 Was sollte dazu beachtet werden? (What should be taken into
consideration?)
2 What you need to know before you <take> <use> X
Do not <take> <use> X<:>
Warnings and precautions
Children <and adolescents>
Other medicines and X
X with <food> <and> <,> <drink> <and> <alcohol>
Pregnancy <and> <,> breast-feeding <and fertility>
Driving and using machines
<X contains {name the excipient(s)}>
5 Wann darf …. nicht eingenommen/angewendet werden?
(When should … not be taken/used?)
6 Wann ist bei der Einnahme/Anwendung von … Vorsicht
geboten? (When should care be taken during use of …?)
7 Darf … während einer Schwangerschaft oder in der Stillzeit
eingenommen/angewendet werden? (Can … be used during
pregnancy or breast-feeding?)
54
Swiss template125
QRD template 948
Section
number
Section heading Section
number
Section heading/Subheading
8 Wie verwenden Sie …? (How should you use …?) 3 How to <take> <use> X
<Use in children <and adolescents>>
<If you <take> <use> more X than you should>
<If you forget to <take> <use> X>
<If you stop <taking> <using> X>
9 Welche Nebenwirkungen kann … haben? (Which side effects
can … have?)
4 Possible side effects
<Additional side effects in children <and
adolescents>>
Reporting of side effects
10 Was ist ferner zu beachten? (What else should be taken into
consideration?)
5 How to store X
11 Was ist in … enthalten? (What is contained in …?) 6 Contents of the pack and other information
What X contains
What X looks like and contents of the pack
Marketing Authorisation Holder and Manufacturer
This leaflet was last revised in <{MM/YYYY}>
<{month YYYY}>.
12 Zulassungsnummer (marketing authorisation number)
13 Wo erhalten Sie …? Welche Packungen sind erhältlich?
(Where can you get ….? Which packets are available?)
14 Zulassungsinhaberin (Marketing authorisation holder)
15 Herstellerin (manufacturer)
16 Diese Packungsbeilage wurde im… (Monat/Jahr) letztmals
55
Swiss template125
QRD template 948
Section
number
Section heading Section
number
Section heading/Subheading
durch die Arzneibehörde (Swissmedic) geprüft. (This package
leaflet was last reviewed by the Drug administration authority
(Swissmedic) in….)
* Sections 1 and 2 of the Swiss template may be swapped on request
56
Headings and fixed text defined in the AMZV125
for homeopathic and anthroposophic medicines are
present in the Swissmedic template for these products and are very similar to those for ‘normal’
prescription and non-prescription medicines. Section 2 is divided into 2a - Name of the product, and 2b -
either homeopathic medicine or anthroposophic medicine, if these terms are not mentioned in the name of
the preparation. When describing the indication the product is used for, the patient is informed that
according to anthroposophic knowledge of humans and nature, or homeopathic principles, that the
medicine can be used for treating the mentioned disorders125
. Sections 5 and 6 are merged into one section
for these types of medicine which then includes all contraindications and precautions. Rubrics which can
be omitted and mandatory information for azo dyes, alcohol and diabetics are identical to other medicinal
products. Article 14 of the AMZV125
includes a fixed statement on the side effects section for homeopathic
medicines that complaints may temporarily become worse (initial aggravation) and that a doctor should be
contacted if the situation persists. The template clearly defines how the active ingredient should be
declared to enable easy identification of the raw material.
Traditional herbal medicines such as teas and tea mixtures, where all information needed for use is
described on the container, are not required to have a package leaflet. For all others, section 2b states
‘Pflanzliches Arzneimittel’ (traditional herbal medicine) which can be omitted if this is contained in the
name of the product. In section 3 ’Was ist... und wann wird es angwendet’ (What is .... and what it is used
for), fixed text differentiates between whether clinically controlled efficacy studies exist for the active
ingredient, or whether the product is traditionally used for the treatment of certain conditions. Sections 5
and 6 are merged into one section. Rubrics which can be omitted and other mandatory information for azo
dyes, alcohol and diabetics are identical to those for other medicinal products.
The patient information for Asiatic drugs is not only regulated by the AMZV125
but also by the
‘Verordnung des Schweizerischen Heilmittelinstituts über die vereinfachte Zulassung von Komplementär-
und Phytoarzneimitteln (Komplementär- und Phytoarzneimittelverordnung, KPAV’177
) (Ordinance of the
Swiss Institute of Therapeutic Products concerning simplified Marketing Authorisations for
Complementary and Herbal Medicinal Products). The KPAV177
states that the patient information for
Asiatic drugs must contain the information in appendix 5.2 of the AMZV125
which relates to homeopathic
and anthroposophic medicines. Appendix 5.4 of the AMZV125
contains additional fixed statements which
must be used for the three types of Asiatic medicines which are distinguished between, namely traditional
Chinese, Tibetan or ayurvedic remedies. Here complete sections of manuscript are provided for the patient
information. The Swissmedic template for Asiatic drugs simply refers the reader to the applicable section
of the AMZV125
and he/she is told to use the fixed statements found there. The European Union QRD
template 9 does not contain any specific wording variations which should be used for homeopathic
57
medicines, traditional herbal medicines or Asiatic drugs; however, the QRD template version 3 intended
for medicines approved via mutual-recognition, decentralised and referral procedures should be used for
these products. National ruling and standard texts do however exist in many countries, for example, in
Germany the content of package leaflets for traditional medicines is regulated in § 11 of German Drug
Law107
.
4.4.2 Comparison of QRD template 9 to the Australian core Consumer Medicine Information
(CMI) template
The core CMI template for product X provides instructions in italics for the CMI writer in a similar
manner to the green text seen in the annotated QRD template 9. A three column format is recommended in
Australia and under each heading, sample statements in bold type are provided from the second edition of
the Usability Guidelines178
which should be chosen or amended as necessary. These guidelines should
continuously be abided by in the CMI and were first developed in 1995 to assist manufacturers when
writing their own patient information, and then revised in 1997. A 3rd
edition of these usability guidelines
was released in 2006 which is only available electronically146
. The Usability Guidelines provide headings,
subheadings, sample statements, and formatting specifications. As in the European Readability
Guideline38
, excessive use of the product name should be avoided by using ‘your medicine. The terms
‘take’, ‘use’, ‘having’ or ‘giving’ should be applied according to the type of product and the active voice
should be used. It is stated that all instructions should be written in bold. Although these extensive
guidance documents, as well as user testing were pioneered in Australia in the 1990s, it is not part of any
legislation.
General notes at the start of the CMI mention the use of a glossary of plain English terms for symptoms of
a disease and side effects which is contained in a document titled ‘Vocabulary for Consumer Medicine
Information’ (CMI)147
. This is available from Medicines Australia and the ASMI (Australian Self
Medication Industry, established in 1974) and is the main body representing companies involved in the
manufacture and distribution of consumer healthcare products in Australia. The vocabulary includes a
medical term followed by the consumer meaning, where possible, with alternative explanations or
descriptions. However, the use of the terms is voluntary and only meant to provide assistance to the CMI
writer. Furthermore, no evidence is provided that these explanations have been tested for
comprehensibility.
58
Table 16: Sections headings and subheadings in the Australian core CMI template in comparison to
QRD template 9
CMI heading143
QRD template 9
heading48
Subheadings in CMI Subheadings in QRD
template 9
What is in this leaflet What is in this leaflet ---- ----
What [Medicine name] is
used for
What X is and what it is
used for
---- ----
Before you
take/use/have/are given
[Medicine name]
What you need to know
before you <take> <use>
X
When you must not take
it
Before you start to take
it
Taking other medicines
Do not <take> <use>
X<:>
Warnings and precautions
Children <and
adolescents>
Other medicines and X
X with <food> <and> <,>
<drink> <and> <alcohol>
Pregnancy <and> <,>
breast-feeding <and
fertility>
Driving and using
machines
<X contains {name the
excipient(s)}>
How to take [Medicine
name]
How to <take> <use> X How much to take
How to take it
When to take it
How long to take it
If you forget to take it
If you take too much
(overdose)
<Use in children <and
adolescents>>
<If you <take> <use>
more X than you should>
<If you forget to <take>
<use> X>
<If you stop <taking>
<using> X> While you are using
[Medicine name]
Things you must do
Things you must not do
Things to be careful of
Things that would be
helpful for ……
59
CMI heading143
QRD template 9
heading48
Subheadings in CMI Subheadings in QRD
template 9
Side effects Possible side effects ----- <Additional side effects
in children <and
adolescents>>
Reporting of side effects
After using [Medicine
name]
How to store X Storage
Disposal
----
Product description Contents of the pack and
other information
What it looks like
Ingredients
Manufacturer
/Distributor/
Supplier
What X contains
What X looks like and
contents of the pack
Marketing Authorisation
Holder and Manufacturer
This leaflet was last
revised in
<{MM/YYYY}>
<{month YYYY}>.
Table 16 shows the great similarity between the CMI template and QRD template 9. At the top of the
Australian Consumer Medicine Information, the user is presented with the title [Medicine name] followed
by ‘Name of the active ingredient’ and for both, the phonetic pronunciation. The QRD template 9 also
starts with the invented name of the product followed by strength and pharmaceutical form. The active
substance(s) is written underneath. There is no provision in the QRD template for phonetic pronunciations
of these terms.
The Australian CMI does not start with an information box at the beginning of the leaflet for prescription
or OTC medicines although the first heading ‘What is in this leaflet’ does include general information
about keeping the leaflet. There is no contents list as in the QRD template 9. The lack of contents list
maybe reflects that the sections in the core CMI are not numbered. The Usability Guidelines however,
provide an illustrated CMI as an example which has a table of contents but notes that it is not necessary
for a CMI of four pages or less146
. When one is included it is shown under the first heading mentioned
above. The main headings presented in the core CMI have been tested by consumers and are therefore
strongly recommended to be used by the Usability Guideline146
. Standard statements contained in the core
CMI are optional and should be tailored to fit a certain product.
60
‘What [Medicine name] is used for’ in the Australian CMI contains information on the therapeutic
indications, how the medicine works and the expected effects of the product in a similar manner to the
information contained in QRD template 9 section 1 ‘What X is and what it is used for’48
. Other additional
sample statements in the Australian CMI under ‘What [Medicine name] is used for’ concern whether the
product is addictive, if the ability to drive is affected and use in children.
‘Before your take/use/have/are given [Medicine name]’ in the Australian CMI143
includes all
contraindications, special warnings and precautions, and interactions with other medicines and is similar
to section 2 of the QRD template 9 ‘What you need to know before you <take> <use> X’48
. Information
regarding pregnancy and breast-feeding is also in this section of the CMI although no specific subheading
is recommended for these topics in the core CMI template. This is contrary to the current QRD template 9
where the subheading ‘Pregnancy <and> <,> breast-feeding <and fertility>‘ is provided in section 248
. A
warning is given in this section of the CMI not to use the medicine after the expiry date printed on the
pack, which is in contrast to the QRD template 9 where this information is presented in section 5 ‘How to
store X’48
. As a precaution, the Australian user is told in the section ‘Before your take/use/have/are given
[Medicine name]’143
to tell the doctor not only about allergies to other medicines but also to foods,
preservatives or dyes which is not reflected in the QRD template 9. However the QRD template mentions
at the end of section 2, on the basis of the excipients guideline, excipients contained in the medicine which
may cause allergies or side effects. As OTC medicines can be bought in Australia not only from
pharmacies, but also from supermarkets or health food shops, consumers are told to tell their doctor or
pharmacist if they are taking medicines purchased from any of these locations.
The section titled ‘How to take [Medicine name]’in the Australian CMI is similar in content to section 3 of
the QRD template 9 ‘How to <take> <use> X’. A difference between the two templates is that the
Australian CMI contains a telephone number for the Poisons Information Centre in the case of an
overdose. Telephone numbers for such institutions in the specific case of an overdose are not included in
the QRD template 9 in this section although some national authorities request their inclusion such as in
Belgium, Finland or Norway179
. Postal and email addresses, websites and in some cases telephone and fax
numbers are however content of section 4 for reporting of side effects in QRD template 9.
The subsequent section in the core CMI template is for ‘While you are using [Medicine name]’ where
precautions are described, such as to tell a doctor or dentist before an operation or blood test and to keep
to doctors’ appointments. The effects on driving and using machines, and children specific warnings
should be included such as riding bicycles or climbing trees. These children specific warnings are not
considered in the European QRD template. The precautions described in this section of the CMI are
61
similar those which are in section 2 of the QRD template 9 under the subheading ‘Warnings and
precautions’. The CMI also include in this section self-help measures for patients to improve their
condition, for example, eating a healthy diet or taking regular exercise. Space for inclusion of such
‘behavioural’ information is not present in QRD template 9.
The section in the CMI ‘While you are using [Medicine name]’ is followed by ‘side effects’ where general
statements are suggested to precede the list. Side effects should be listed in order of urgency of the
behaviour required, namely most serious first. This is similar to section 4 of the QRD template 9 where the
most serious side effects are listed first. Only those symptoms which the consumer can detect and do
something about should be included in the CMI.
‘After using [Medicine name]’ follows the side effect section in the CMI. This is product specific and
describes storage and disposal statements. The CMI ends with the ‘Product description’. Interestingly, a
list of excipients is included which are not contained in the product rather than those with known effects
as is the case in the QRD template 9. The CMI contains the sentence ‘This medicine does not contain
lactose, sucrose, gluten, tartrazine or any other azo dyes’ and the writer is instructed to include any others
that are appropriate. In Australia, it is not a requirement to list excipients which may affect the safe use of
the product in the CMI, but only on the label. This is regulated by the Therapeutic Goods Order No. 69
which was compiled under section 10 of the Therapeutic Goods Act 1989180
, and defines the requirements
for labels for medicines. In Schedule 1 of the order, excipients required to be declared on the label of
medicines are listed along with the conditions and special labelling requirements.
4.4.3 Comparison of QRD template 9 to the New Zealand core Consumer Medicine Information
(CMI) template
The core CMI152
in New Zealand is very similar to that in Australia making it also very similar to the QRD
template 9 as shown in table 17, although the detail provided for the pharmaceutical company on how to
fill in the relevant information is very sparse. As seen in the Australian CMI template, under the first
heading ‘What is in this leaflet’ general information is included about keeping the leaflet rather than the
contents list as in the QRD template 9. The New Zealand CMI template differs from the Australian CMI
in that separate section headings are provided for overdose, sponsor details and date of preparation of the
leaflet. This information is integrated under different section headings in the QRD template 9.
62
Table 17: Sections headings and subheadings in the New Zealand core consumer medicine
information (CMI) template in comparison to QRD template 9 headings and subheadings
CMI heading in
bold152
QRD template 9
heading48
Subheadings in
CMI
Subheadings in QRD
template 9
What is in this leaflet What is in this leaflet ---- ----
What [Trade name] is
used for
What X is and what it
is used for
---- ----
Before you use [Trade
name]
What you need to
know before you
<take> <use> X
When you must not
use it
Before you start to
use it
Taking other
medicines
Do not <take> <use> X
Warnings and precautions
Children <and
adolescents>
Other medicines and X
X with <food> <and> <,>
<drink> <and> <alcohol>
Pregnancy <and> <,>
breast-feeding <and
fertility>
Driving and using
machines
<X contains {name the
excipient(s)}>
How to use [Trade
name]
How to <take> <use>
X
How much to take
When to take it
How long to take it
If you forget to take
it
<Use in children <and
adolescents>
<If you <take> <use>
more X than you should>
<If you forget to <take>
<use> X>
<If you stop <taking>
<using> X>
While you are using
[Trade name]
Things you must
do
Things you must
not do
Things to be careful
of
In case of overdose If you take too
much (overdose)
63
CMI heading in
bold152
QRD template 9
heading48
Subheadings in
CMI
Subheadings in QRD
template 9
Side effects Possible side effects ---- <Additional side effects
in children <and
adolescents>>
Reporting of side effects
After using [Trade
name]
How to store X Storage
Disposal
Product description Contents of the pack
and other information
What it looks like
Ingredients
Manufacturer
/Distributor/
Supplier
What X contains
What X looks like and
contents of the pack
Marketing Authorisation
Holder and Manufacturer
This leaflet was last
revised in
<{MM/YYYY}>
<{month YYYY}>.
Sponsor details ----
Date of preparation ----
4.4.4 Comparison of QRD template 9 to the different templates used in the Unites States for
patient information
4.4.4.1 Analysis of the content of the labelling for prescription medicines in the United States
The new labelling for prescription medicines is not incorporated into the following comparison of
templates used in the United States to the QRD template 9, as this information is mainly intended for use
by clinical professionals, as detailed pharmacology and patient counselling information sections are
included166
. Details on the regulations regarding prescription medicines were given in section 4.3.6 to
provide a better overview of the situation in the United States regarding printed medicine information. The
MedGuide and drug facts labelling for OTC medicines can be considered to be templates as set headings
are defined as well as the content which should be included. Although the CMI does not take on the form
of a template with respect to defined headings, the content and how it should be presented are clearly
described although not legally binding159
.
64
4.4.4.2 Information required in a medication guide (MedGuide)
The Code of Federal Regulations Title 21 Part 208 describes the general requirements for a medication
guide163
. The headings stated in the regulations should be used in the defined order if appropriate to the
product. The phonetic spelling of either the brand name or established name should be included. No
contents list or numbered sections are contained in the MedGuide in contrast to the QRD template 9. The
first heading ‘What is the most important information I should know about (name of drug)?’ describes the
particular serious and significant public health concern that has created the need for the medication guide
and statements should inform the patient on how to weigh up the benefits against the risks of using the
medicine. Such information is not included in the QRD template 9. In the MedGuide, the headings are all
written as a series of questions and clear instructions are given on which statements must be included. The
nature of the disease or condition the drug product is intended to treat, as well as the benefits of treating
the condition are allowed to be described under ‘appropriate circumstances’163
, although these situations
are not defined. The QRD template 9 also allows ‘on a case-by-case basis’ that information on the benefits
of the treatment can be included50
.
4.4.4.3 Content of Consumer Medication Information (CMI)
In 2006, the FDA issued a non-binding guideline in collaboration with the Center for Drug Evaluation and
Research (CDER) and Center for Biologics and Research (CBER) to assist the writers of Consumer
Medication Information (CMI)159
. CMIs are intended for prescription only drugs and since the FDA does
not personally approve this information, the guidance was hoped to help ensure that CMIs are useful to
consumers. To this end, the eight criteria developed in the action plan162
were listed and recommendations
to satisfy these criteria were presented. Criteria 1 to 6 involved the contents of the CMI, while 7 and 8
assessed whether the information is scientifically accurate, unbiased and up-to-date as well as being
legible and comprehensible to users. The guidelines include no set section headings or subheadings in
contrast to the QRD template 9 but rather detailed guidance on how and which information should be
presented. It is recommended including all approved indications and contraindications in the package
leaflet but not a full listing of all possible side effects. The most serious should appear plus a statement
telling patients that the list is not complete. A disclaimer should also be included that the CMI is a
summary and does not contain all possible information. The main sections to be included in the CMI are
indications, contraindications, directions for use and storage, precautions and side effects which are also
contained in the QRD template 9.
4.4.4.4 Information intended for over-the-counter (OTC) medicines
OTC medicines are considered by the FDA to be safe and effective for the general public to use without a
prescription. These drugs are not obliged to include a package leaflet but must abide by the Drug Facts
65
labelling requirements in the Code of Federal Regulations Title 21154
which were defined by the FDA in
1999181
, whereby information is printed on the immediate packaging or outside container under the
heading ‘Drug Facts’. The title ‘Drug Facts’ is compulsory in a standardised format as this is stated to
provide an important visual cue for introducing required information. The Drug Facts label is in the form
of a template with mandatory headings specified to be written in bold type for inclusion of information on
the product's active ingredient(s), indications and purpose, safety warnings, directions for use, and inactive
ingredients as a series of short sentences or single words separated by bullet points. The Drug Facts
template is a much more concise document than the QRD template 9 and is more a short list of details
about the medicine. The sections contained are the same as in the QRD template 9 although directions for
use are located at the end of the label rather than in section 3 as in the QRD template.
A comparison of the content and order of the information in these three documents used in the United
States with QRD template 9 is shown in table 18. All patient information templates start with the name of
the product and active ingredient. The basic content of the patient information in the United States is
similar in all documents to that of the European QRD template 9 but varies in how much detail is provided
for the user. The order of information contained is most similar between the MedGuide and the QRD
template 9. Whereas the medication guide provides a series of questions as headings, the others all use
brief statements pertaining to the contents of the section as in the QRD template 9. Use of standard or
fixed statements is not commonly seen in the United States and only one verbatim statement that
‘Medicines are sometimes prescribed for purposes other than those listed in a medication guide’ is defined
in the legislation for MedGuides. Only common side effects are usually described without a definition of
frequency. A number of standard warning statements are defined for OTC medicines such as ‘allergy
alert’ or ‘choking’ for gums. The CMI is the only US document to describe to patients how to monitor
themselves for an improvement in their condition. This is not reflected in the QRD template 9.
66
Table 18: Comparison of the content and order of information contained in the Medication Guide,
CMI, labelling of OTC medicines and the QRD template 9
Medication Guide163
CMI159
OTC medicines154
-
Drug facts
QRD template 948
Brand name and
phonetic spelling
Drug names, approved
uses, and what to watch
for to see if you are
getting better
Active ingredient {(Invented) name
strength
pharmaceutical form}
{Active substance(s)}
What is the most
important information
I should know about
(name of drug)?
Contraindications Purpose (general
pharmacological
category)
What X is and what it
is used for
What is (name of
drug)?
How to use and store the
medicine and what to do
in case of overdose
Uses
Who should not take
(name of drug)?
Specific warnings and
things to watch for about
the medicine
Warnings What you need to
know before you
<take> <use> X
(Section for
contraindications,
warnings and
precuations)
How should I take
(name of drug)?
Symptoms of serious or
frequent adverse reactions
and what to do
Do not use How to <take> <use>
X
What should I avoid
while taking (name of
drug)?
General information such
as when to talk to doctor
Ask a doctor before
use if you have
What are the possible
or reasonably likely
side effects of (name
of drug)?
When using this
product
Possible side effects
Name and place of
business of the
Stop use and ask a
doctor if
How to store X
67
Medication Guide163
CMI159
OTC medicines154
-
Drug facts
QRD template 948
manufacturer, packer,
or distributor
The date of the most
recent revision of the
medication guide
Directions Contents of the pack
and other information
This leaflet was last
revised in
<{MM/YYYY}>
<{month YYYY}>.
Other information
Inactive ingredients
Questions
4.5 Comparison of QRD template 9 to other templates published by non-EU countries
The use of a template for the package leaflet provides advantages as a standard format and set order make
it easier for the user to locate particular information as the information provided with all medicines
information is identical in structure. The order and content of information contained in the template for the
package leaflet from Switzerland, templates for Consumer Medicine Information in Australia and New
Zealand, United States Medication Guides and in the European QRD template 9 is surprisingly similar as
shown in table 19. The Swiss template and QRD template are the only documents in the comparison
which use numbered sections and an information box at the start of the leaflet. The Swiss template shows
the most detailed subdivision of information with the greatest number of section headings of any of the
compared templates. A contents list is only seen in the QRD template. CMI from Australia and New
Zealand should also however use numbered sections and a contents table when the leaflet is longer than 4
pages. The Swiss template uses questions as title headings while all others all use brief sentences relating
to the content of the section. In general all templates start with what the medicine is used for, followed by
contraindications, warnings and precautions, how to use the medicine and side effects. Information such as
a description of the product, manufacturer, marketing authorisation holder and date of approval of the
leaflet are located in all templates near the end of the template. The QRD template 9 and those for the
CMI in Australia and New Zealand allow for a description of the benefits of using the medicine. Self-help
methods to improve the present health condition are allowed for in Australia, New Zealand and
Switzerland. Whether a product is addictive and use of phonetic spellings are also seen in the CMI
template in Australia and New Zealand. Whereas a subheading in QRD template 9 is present for
declaration of excipients defined in the Excipients Guideline94
, excipients to which a patient might react to
are only described on the labelling of the product in Australia and New Zealand. The Swiss template only
makes allowance for declaration of allergy to food preservatives or dyes.
68
Table 19: Comparison of QRD template 9 to templates from Switzerland, Australia, New Zealand and the USA
Swiss template129
QRD template 948
CMI Australia143
CMI New Zealand152
US Medication Guide163
Section heading/Subheading
1. Information für Patientinnen
und Patienten* (Information for
patients)
{(Invented) name strength
pharmaceutical form}
{Active substance(s)}
Information box
prescription/OTC medicines and
index ‘What is in this leaflet’
What is in this leaflet What is in this leaflet Brand name and phonetic
spelling
2 (a) Name des Präparates* (Name
of the product)
What is the most
important information I
should know about (name
of drug)?
3. Was ist … und wann wird es
angewendet? (What is …. and what
it is used for)
1. What X is and what it is
used for
What [Medicine name]
is used for
What [Trade name] is
used for
What is (name of drug)?
4. Was sollte dazu beachtet
werden? (What else should be taken
into consideration?)
2. What you need to know
before you <take> <use> X
Do not <take> <use> X<:>
Warnings and precautions
Children <and adolescents>
Other medicines and X
X with <food> <and> <,>
<drink> <and> <alcohol>
Before you
take/use/have/are given
[Medicine name]
When you must not take it
Before you start to take it
Taking other medicines
Before you use [Trade
name]
When you must not use
it
Before you start to use it
Taking other medicines
Who should not take
(name of drug)?
5. Wann darf …. nicht
eingenommen/angewendet
werden? (When should … not be
taken/used?)
6. Wann ist bei der
69
Swiss template129
QRD template 948
CMI Australia143
CMI New Zealand152
US Medication Guide163
Section heading/Subheading
Einnahme/Anwendung von …
Vorsicht geboten? (When should
care be taken during use of …?)
Pregnancy <and> <,> breast-
feeding <and fertility>
Driving and using machines
<X contains {name the
excipient(s)}>
7. Darf … während einer
Schwangerschaft oder in der
Stillzeit eingenommen/angewendet
werden? (Can … be used during
pregnancy or breast-feeding?)
8. Wie verwenden Sie …? (How
should you use …?)
3. How to <take> <use> X
<Use in children <and
adolescents>>
<If you <take> <use> more X
than you should>
<If you forget to <take> <use>
X>
<If you stop <taking> <using>
X>
How to take [Medicine
name]
How much to take
How to take it
When to take it
How long to take it
If you forget to take it
If you take too much
(overdose)
How to use [Trade
name]
How much to take
When to take it
How long to take it
If you forget to take it
How should I take (name
of drug)?
70
Swiss template129
QRD template 948
CMI Australia143
CMI New Zealand152
US Medication Guide163
Section heading/Subheading
While you are using
[Medicine name]
Things you must do
Things you must not do
Things to be careful of
Things that would be
helpful for ……
While you are using
[Trade name]
Things you must do
Things you must not do
Things to be careful of
What should I avoid
while taking (name of
drug)?
In case of overdose
If you take too much
(overdose)
9. Welche Nebenwirkungen kann
… haben? (Which side effects can
… have?)
4. Possible side effects
<Additional side effects in
children <and adolescents>>
Reporting of side effects
Side effects Side effects What are the possible or
reasonably likely side
effects of (name of drug)?
10. Was ist ferner zu beachten?
(What else should be taken into
consideration?)
5. How to store X After using [Medicine
name]
Storage
Disposal
After using [Trade
name]
Storage
Disposal
11. Was ist in … enthalten? (What
is contained in …?)
6. Contents of the pack and
other information
Product description
What it looks like
Product description
What it looks like
71
Swiss template129
QRD template 948
CMI Australia143
CMI New Zealand152
US Medication Guide163
Section heading/Subheading
12. Zulassungsnummer (Marketing
authorisation number)
What X contains
What X looks like and contents
of the pack
Marketing Authorisation Holder
and Manufacturer
Ingredients
Manufacturer/Distributor/
Supplier
Ingredients
Manufacturer/Distribut
or/Supplier Name and place of
business of the
manufacturer, packer, or
distributor 13. Wo erhalten Sie …? Welche
Packungen sind erhältlich?
(Where can you get ….? Which
packets are available?)
This leaflet was last revised in
<{MM/YYYY}> <{month
YYYY}>.
Sponsor details
14. Zulassungsinhaberin
(Marketing authorisation holder)
Date of preparation
15. Herstellerin (manufacturer)
16. Diese Packungsbeilage wurde
im… (Monat/Jahr) letztmals
durch die Arzneibehörde
(Swissmedic) geprüft. (This
package leaflet was last reviewed by
the Drug administration authority
(Swissmedic) in….)
The date of the most
recent revision of the
Medication Guide
72
4.6 Analysis of QRD template implementation in package leaflets of centralised approved
medicines
On the evening of 21.10.2011 to 23.10.2011, package leaflets in the English language of centralised
approved human medicines were downloaded from the EMA website. Of the 616 package leaflets which
were downloaded it was possible to analyse 565. The other 51 could either not be converted into Word
documents, large passages of text remained as pictures or caused the Microsoft Office Word 2007
program to continually crash. Authorisation dates for the analysable medicines ranged from 20.10.1995 to
03.10.2011 and the number of revisions of the documentation was up to 38 times.
The second download took place on 03.10.2012. Of the 565 package leaflets which were analysable in the
first download, 423 had been updated at the time of the second download (74.9 %). The authorisation for
none of these medicines had been either suspended or withdrawn. The 423 package leaflets were therefore
downloaded from the EMA website to be analysed and compared to the leaflets in the first download.
Leaflets from the first download which had not been altered since this date were integrated into the data
set for analysis.
The third download took place on 07.10.2013. Of the 565 package leaflets which were analysed in the first
and second download, 411 had been updated since the second download (72.7 %), 118 had not been
updated (20.9 %), 34 products had been withdrawn and 2 had been suspended (6.4 %). The package
leaflets for these 36 withdrawn or suspended medicines were therefore subsequently removed from the
data set used for analysis as they had not been developed further. The 411 updated leaflets were
downloaded from the EMA website to be analysed and compared to the leaflets in the first and second
downloads. Leaflets from the first and second downloads which had not been altered were again integrated
into the data set for analysis.
4.6.1 Types of medicines registered using the centralised authorisation procedure at the EMA
Most of the medicines of the analysed package leaflets in the first download were available only on
prescription (98.9 %) while six were available over-the-counter. The types of medicine were also sorted
into pharmaceutical forms. The most common type according to pharmaceutical form noted in the package
leaflets were products for parenteral administration (injections and infusions) and film-coated tablets
(table 20).
The calculation of the 95 % confidence interval showed that the percentage of package leaflets in the
initial sample of 616 documents always fell between the upper and lower limits of the confidence interval
range for all groups within each three of the defined categories (tables 20 and 21). It can therefore be
73
concluded that the analysed sample of 565 package leaflets is representative of the initial sample of 616
package leaflets and thereby consequently representative of the package leaflets for all centralised
approved human medicines on the EMA website.
Table 20: Distribution of the analysed 565 package leaflets according to prescription status and
pharmaceutical form of the medicines in the first package leaflet download from the EMA website
including the complete sample of 616 package leaflets
Assessed
component
Sample of 565 package leaflets Initial sample of
616 package
leaflets
(%)
n % 95 % confidence
interval
Sales status
Prescription only 559 98.9 98.1 – 99.8 99.0
OTC 6 1.1 0.2 – 1.9 1.0
Pharmaceutical form
Film-coated
tablets
152 26.9 23.2 – 30.6 27.9
Parenteral
administration
forms
209 37.0 33.0 - 41.0 37.5
All other tablets
including
dispersible,
buccal, prolonged
release
79 14.0 11.1 – 16.8 12.8
All capsules
including soft,
hard, gastro-
resistant
61 10.8 8.2 – 13.4 11.2
Others (e.g. nasal
spray, eye drops,
transdermal
plasters)
64 11.3 8.7 – 13.9 10.6
74
When examining the first letter of the ATC code of the medicines in the first download, the most
commonly represented anatomical group was antineoplastic and immunomodulating agents (ATC code
starting with L) followed by antiinfectives for systemic use (ATC code starting with J) (table 21).
Table 21: Percentage of package leaflets in the first download which were analysed, and the
complete sample of 616 package leaflets downloaded from the EMA website, relating to the
anatomical main group of medicines according to ATC code
First
letter of
ATC
code
Drug classification Sample of 565 package leaflets Initial
sample of
616 package
leaflets
(%)
n %
95 %
confidence
interval
A Alimentary tract and
metabolism
72 12.7 10.0 – 15.5 12.0
B Blood and blood forming
organs
60 10.6 8.1 – 13.2 10.9
C Cardiovascular system 50 8.8 6.5 – 11.2 8.4
D Dermatologicals 5 0.9 0.1 – 1.7 0.8
G Genito-urinary system and
sex hormones
30 5.3 3.5 – 7.2 5.4
H Systemic hormonal
preparations, excluding sex
hormones and insulins
11 1.9 0.8 – 3.1 1.8
J Antiinfectives for systemic
use
90 15.9 12.9 – 18.9 16.2
L Antineoplastic and
immunomodulating agents
111 19.6 16.4 – 22.9 19.6
M Musculo-skeletal system 21 3.7 2.2 – 5.3 3.7
N Nervous system 68 12.1 9.4 – 14.7 12.7
R Respiratory system 13 2.3 1.1 – 3.5 2.1
S Sensory system 10 1.9 0.7 – 2.9 2.3
V Various (e.g.
radiopharmaceuticals for
diagnosis, iron chelators)
24 4.3 2.6 – 5-9 4.1
75
4.6.2 Use of the contents list and sentences contained in the information box at the start of the
QRD template for the package leaflet
All package leaflets in the first download were determined to have used QRD template 7. Although there
are 5 different subversions of QRD template edition 7, none of the minor changes existing between these
template versions affected the elements which were analysed in this study, meaning that a further
subdivision of package leaflets with QRD template 7 into sub-editions of this template version was not
carried out.
Six of the 565 examined contents lists in the first download were not completely QRD template conformal
as instead of the standard 6 sections, section 4, for example, was used for information for diabetics.
Consequently the information normally included in sections 4, 5 and 6 was moved into sections 5, 6 and
an additional section 7. In four other cases, point 7 was also included in the contents list for further
information or patient instructions.
Two package leaflets in all three downloads contained subheadings in the contents list which increased the
number of words for the standard contents list from approximately 36 to 161 words in one case and in the
other to 149 words. In all downloads, six of the examined leaflets did not contain a contents list but due to
other aspects of template wording present in the package leaflets, these were designated to have used QRD
template 7 (table 22). In the second download, 183 of the 559 leaflets with a contents list, contained the
contents list according to QRD template 8. In the third download, 278 of the 523 leaflets with a contents
list contained the list which was first described in QRD template 8, and a further 81 package leaflets had
the new paragraph from QRD template version 9 regarding the reporting of side effects to the national
authorities. Of these 81 leaflets, 21 had the black symbol for ‘additional monitoring’ resulting from
Directive 84/2010/EU42
. A cross-reference to ‘see section 4’ is included in the information box from QRD
template 9 to aid patients in locating potential side effects. In the third download, 59 leaflets from the 529
studied had a reference to section 4 in the information box (4 with QRD template 8 in the absence of the
new section for reporting side effects, and 55 with QRD template 9).
76
Table 22: Package leaflets downloaded from the EMA website assessed relating to the presence of
contents list, inclusion of section ‘Reporting side effects’ and points in the information box of the
QRD template
Aspect contained in the
package leaflet
Percentage package leaflets with the wording provided in the
left column (%)
Download 1
(n = 565)
Download 2
(n = 565)
Download 3
(n =529)
Contents list 99.0 99.0 98.9
Package leaflets using
QRD template 7
100 67.6 32.1
Package leaflets using
QRD template 8
0 32.4 52.6
Package leaflets with
QRD template 9 section
‘Reporting side effects’
0 0 15.3
Info box point 1 100 100 100
Info box point 2 100 100 100
Info box point 3 85.0 82.7 82.4
Info box point 4 100 100 100
The information box was present in all package leaflets although not always template conformal. In the
first download, seven package leaflets included extra information, for example, regarding patient alert
cards and in one case the patient was told to refer to the SmPC as the package leaflet did not contain all
the information about the medicine. Points 1, 2 and 4 were always present in all downloads, whereas point
3 was absent in 15.0 to 17.6 % of the leaflets (table 22). Point 3 contains the information for prescription
only medicines that ‘This medicine has been prescribed for you. Do not pass it on to others. It may harm
them, even if their symptoms are the same as yours’48,49,51
. This point is in pointed brackets in template
versions 7, 8 and 9 meaning that it can be omitted. Where it was absent, the fact that the patients may
never handle the medicine themselves had been taken into consideration, which is reflected by the type of
product (table 23). Some products which are injected can be administered by the patient after appropriate
instructions from a doctor or healthcare professional. Leaflets for these medicines usually contained
patient information on ‘how to inject yourself’ at the end of the leaflet or detailed instructions in section 3
‘How to take X’48,49,51
.
77
Table 23: Percentage of package leaflets downloaded from the EMA website according to medicine
type where point 3 in the information box of the QRD template had been omitted
Type of medicine Percentage of package leaflets according to type of
medicine (%)
Download 1
(n = 85)
Download 2
(n = 98)
Download 3
(n = 93)
Parenteral administration forms 81.2 82.6 85.9
Radiopharmaceuticals 4.7 4.1 3.2
Others (e.g. capsules, medicated
sponge, inhalation gas, sealant)
14.1 13.3 10.9
QRD template 7 offers the choice of the words ‘doctor’ and/or ‘pharmacist’ in point 2 of the information
box at the beginning of the package leaflet which was extended to include ‘nurse’ from QRD template 8.
Point 2 of the information box was therefore further analysed to see which terms were preferred (table 24).
Table 24: Percentage of package leaflets downloaded from the EMA website assessed according to
terms used in point 2 of the information box of the QRD template
Terms used in point 2: If you have any
questions ask your...
Percentage package leaflets with the wording provided in
the left column (%)
Download 1
(n = 565)
Download 2
(n = 565)
Download 3
(n = 529)
Doctor or pharmacist 82.3 71.9 64.7
Doctor 8.6 8.7 7.9
Doctor, pharmacist or nurse/healthcare
professional
5.1 15.2 23.4
Doctor or nurse 1.5 2.1 3.0
Other (e.g. nuclear medicine specialist,
anaesthetist, midwife, doctor or
healthcare professional)
2.3 2.1 0.9
78
Use of the terms ‘doctor or pharmacist’ was most common. Use solely of the term ‘doctor’ or additional
names such as ‘surgeon’ or ‘anaesthetist’ reflected the nature of the product. In the second and third
downloads, use of the three terms ‘doctor, pharmacist or nurse/healthcare professional’ greatly increased.
4.6.3 Number of words caused by the QRD template, the list of local representatives of the
marketing authorisation holder, additional information for patients and health professionals
The number of words in each package leaflet from each download were counted. Although only a few
package leaflets were available with last approval date between 2007 and 2009, the general trend shows
that the total number of words and the number of words caused by the QRD template had increased up to
the present day in the patient information (table 25).
The total number of words in the examined leaflets from the first download ranged from 799 to 6249, 808
to 7776 in download 2 and 1078 to 7822 in the third download. In the QRD template, X should be
replaced by the medicine name which means that a long product name could influence the word count. In
no cases were the pharmaceutical form and dosage strength written throughout the leaflet, but found only
at the top of the package leaflet. Most product names consisted of one or two words. For two vaccines in
the three downloads, however, the product names contained 5 and 10 words respectively. In the case that a
10 word product name is included the maximum of 24 times in a leaflet written according to QRD
template version 7, the number of words is increased by 216 in comparison to a one word name. Through
the use of the term ‘this medicine’ in QRD templates 8 and 9, the number of times the product name is
mentioned is reduced to a maximum of 19. Product names used outside the QRD template text are not
considered in the found numbers.
Although the QRD template states at the end of the leaflet after section 6 ‘The following information is
intended for healthcare professionals only:’ in some cases, this section also contained information for
patients which contributed to a large extent in the amount of the total text. Three package leaflets in the
first download, one in the second download and seven in the third download contained information both
for the patient and healthcare professionals. Information for patients on how to administer the medicine
themselves or ways of improving their condition, and for healthcare professionals on how to give the
medicine or store it accounted for up to 64.7 % and 50.5 % respectively of the total words in the first
download, 66.8 % and 51.9 % in the second download and 67.3 % and 53.7 % in the third download (table
26). In the case where only 0.8 % of the text of the leaflet contained information for healthcare
professionals, the doctor was simply told to refer to the SmPC.
79
Table 25: Date of last update of the product information and average number of total words and
QRD template plates contained in the package leaflets of centralised approved medicines
downloaded from the EMA website
No. of
leaflets
Year of last
update
Percentage
of
products
(%)
Average
no. total
words
Average
no. total
words
per
download
Average no.
QRD template
words*
Average no.
QRD template
words* per
download
Download 1
(n = 565)
2007 0.9 1886 2436 372 444
2008 0.5 2485 402
2009 4.2 1984 431
2010 13.7 2229 444
2011 (up to
21.10.2011)
80.7 2501 446
Download 2
(n = 565)
2007 0.6 1674 2576 389 468
2008 0 - -
2009 1.6 1838 389
2010 3.7 2226 443
2011 24.2 2561 453
2012 (up to
03.10.2012)
69.9 2574 477
Download 3
(n = 529)
2007 0.2 1347 2638 314 499
2008 0 - -
2009 0.6 1774 372
2010 0.8 2127 423
2011 4.9 2380 465
2012 22.5 2636 473
2013 (up to
07.10.2013)
71.0 2672 511
* The number of words from the list of MAH representatives was not included in this analysis
80
Table 26: Analysis of the number of words contained in package leaflets downloaded from the EMA
website with regard to additional patient text, information for healthcare professionals, QRD
template text for each template version and the address list for representatives of the marketing
authorisation holder
Aspect contained
in the package
leaflet
Download Leaflets
with text
(%)
Minimum
words
Maximum
words
Average
words
Percentage
(%) of total
words
Additional
Patient
information text
1 10.6 56 2569 955 3.0 - 64.7
2 9.7 53 5192 883 2.8 - 66.8
3 11.7 56 5264 938 2.7 - 67.3
Healthcare
professional
information
1 24.4 12 1982 416 0.8 - 50.5
2 23.9 12 2107 455 0.8 - 51.9
3 24.6 12 2155 429 0.6 - 53.7
Words caused by
QRD template*
(without list of
MAH
representatives)
1 - QRD template
7 (n = 565)
100 256 596 444 6.7 - 39.4
(average 19.7)
2 - QRD template
7 (n = 382)
67.6 286 623 450 6.4 - 39.9
(average 19.6)
2 - QRD template
8 (n = 183)
32.4 289 627 509 7.2 - 34.1
(average 20.5)
3 - QRD template
7 (n = 170)
32.1 314 591 451 6.7 - 39.0
(average 20.0)
3 - QRD template
8 (n = 278)
52.6 289 610 509 7.2 - 38.2
(average 20.3)
3 - QRD template
9 (n = 81)
15.3 408 643 565 11.9 - 34.8
(average 21.5)
List of MAH
representatives
1 82.3 18 559 249 1.0 - 33.3
(average 13.0)
2 84.2 18 637 311 0.6 - 31.2
(average 12.8)
3 85.8 19 639 311 0.6 - 33.6
(average 12.4)
* Leaflets without a contents list were designated to have used QRD template 7
81
The number of words caused by the text printed in the QRD template in black of the first download ranged
from 256 to 596 (average 444, table 26). This accounted here for up to 39.4 % of the total text. In the
second and third downloads, the number of words in each package leaflet caused by the QRD template
was analysed according to whether the leaflet used QRD template version 7, 8 or 9. The average number
of words caused by the templates had increased with increasing version number. The volume of text
increase was approximately by 10 % between leaflet versions. However, the maximum percent of the total
words caused by the templates decreased in the second and third downloads when comparing the leaflets
with template 7 and 8 in the second download and template 8 and 9 in the third download, even though the
maximum QRD template words had increased. The minimum number of words caused by QRD template
9 is increased by 119 words in comparison to leaflets with QRD template 8.
QRD template 7 contains approximately 640 words (depending on subversion number) while QRD
template 8 contains a maximum of 771 words (see section 4.1.1) and QRD template 9, 840 words. From
the first download, leaflets therefore used a maximum of 69 % of the QRD template 7 text. In the second
download leaflets with QRD template 8 used a maximum of 66 % of the provided text. In the third
download leaflets with QRD template 9 used a maximum of 67 % of the template text.
4.6.4 Reference in section 2 to section 6 for location of the list of other ingredients
In section 2 of the package leaflet for QRD template version 7, patients were told not to take the medicine
if they were ‘allergic (hypersensitive) to the active ingredient or any of the other ingredients’51
. QRD
templates 8 and 9 now tell the patient where to find the list of other ingredients, namely in section 6.
Although all examined leaflets in the first download were QRD template version 7 according to the
wording of the contents list, many already included a reference to section 6. Wording here varied between
leaflets but in many cases the patient was told directly to refer to section 6, or alternatively ‘the list of
ingredients contained at the end of the leaflet’. 39.1 % of the leaflets contained a reference in some form
as to where to find the excipients. In the second download, 56.4 % of the 565 leaflets contained a
reference to section 6 regardless of whether QRD template 7 or 8 had been used and in the third download,
74.1 % had a reference. However, a subanalysis of the leaflets in the second download with QRD template
8 showed that 10.9 % of these had no reference to section 6 and 6.3 % in the third download of the leaflets
with QRD templates 8 or 9.
4.6.5 Method of presenting the frequency of side effects
No specific structure for the side effect section of the package leaflet was recommended in QRD template
7. This was updated from version 8 where a clear organisation of the information is recommended
whereby the most serious side effects should be listed first with instructions for what action the patient
should take. This was first suggested in the sample package leaflet contained in the Readability Guideline
82
from 199836
and again in the revised version in 200938
in the ‘Recommendations for the package leaflet’
section. Table 27 shows that nearly half the examined package leaflets in the first download listed the
most serious side effects first. This had increased to 74.3 % of the package leaflets in the second download
which used QRD template 8 and 79.0 % in the third download for package leaflets with QRD template 9.
The patient was usually told to stop taking the medicine straight away and contact their doctor
immediately.
The use of MedDRA system organ classes is standard in the SmPC but they are not suggested for the
package leaflet, although 0.9 % of the examined package leaflets in the first download did use organ
systems. The remaining 99.1 % used side effect frequencies to categorise side effects. In download 2 and
3, organ classes were never used in the side effect section of the package leaflet.
Table 27: Analysis of package leaflets downloaded from the EMA website regarding location of
severe side effects and form of presentation of side effect frequency explanations
Presentation
of side
effects
Percentage package leaflets with the aspect provided in the left column (%)
Download 1
QRD
template 7
(n = 565)
Download 2
QRD
template 7
(n = 382)
Download 2
QRD
template 8
(n = 183)
Download 3
QRD
template 7
(n = 170)
Download 3
QRD
template 8
(n= 278)
Download 3
QRD
template 9
(n = 81)
Severe side
effects listed
first
46.4 51.6 74.3 52.9 73.7 79.0
Frequencies
in table or
list at start
of section 4
49.4 51.3 7.7 45.9 10.4 23.5
Frequencies
as part of
the side
effect list
46.9 44.5 90.7 47.6 88.8 74.0
Other form
of side effect
frequency
presentation
3.7 4.2 1.6 6.5 0.8 2.5
83
A specific convention for the description of side effect frequencies is recommended for the first time in
QRD template 8 where it was additionally advised that ‘This frequency convention should not appear
before the list of side effects as this takes up space and has shown in user testing to be misleading to
patients’56
. The two main methods used were to note frequency explanations in the form of a table at the
start of section 4, or present them as part of the side effect list where a particular frequency is noted
followed by a record of all side effects in this category. The preferred method for describing frequency in
the first download was as a table. In the second and third downloads, most package leaflets with QRD
templates 8 and 9 had listed the frequencies as part of the side effect list (table 27).
Table 28: Analysis of the method of description of the frequency of side effects in package leaflets
downloaded from the EMA website
Method of frequency
description of side
effects
Percentage of package leaflets containing side effect frequency description
method in left column (%)
Download 1
QRD
template 7
(n = 565)
Download 2
QRD
template 7
(n = 382)
Download 2
QRD
template 8
(n = 183)
Download 3
QRD
template 7
(n = 170)
Download 3
QRD
template 8
(n= 278)
Download 3
QRD
template 9
(n = 81)
Common: affects 1 to
10 per 100 users
(BfArM
recommendation120
/
EMA report 2007182
)
66.6 65.4 17.4 57.7 16.2 14.8
Common: May occur
in up to 1 in 10 users
(QRD template
8/950,56
)
14.8 17.3 76.0 22.9 78.8 79.0
Common: less than 1
per 10 but more than
1 per 100 users
(Readability
Guideline, 199836
)
10.5 8.1 3.3 6.5 0.7 0
Other 8.1 9.2 3.3 12.9 4.3 6.2
84
The majority of package leaflets in the first download used the side effect explanation type ‘common,
affects 1 to 10 per 100 users’ (table 28) which is described by BfArM120
and the EMA182
. The next most
commonly used description type was ‘common: may occur in up to 1 in 10 users’ which is similar to the
recommendation of QRD templates 8 and 9 namely ‘Common: may affect up to 1 in 10 people’50,56
. In the
second download, the BfArM/EMA defined description from 2007 of side effects was still used most
frequently for package leaflets using QRD template 7, however those using QRD template 8 mostly used
the frequency convention described in the annotated version of this template. The third download also
showed that package leaflets with QRD template version 8 or 9 most commonly used the recommendation
described since publication of QRD template 8 (table 28).
QRD templates 8 and 9 mention in the annotated version that double sided expressions such as 'common,
less than 1 per 10 but more than 1 per 100' are not well understood50,56
. This method of description was
used in 10.4 % of examined package leaflets in the first download but decreased in both the second and
third downloads regardless of which template version had been used (table 28).
4.6.6 Text headings and standard statements in section 2 of the package leaflet
The first bullet point in section 2 of the package leaflet differs between QRD template 7 and 8/9. In QRD
template 7, the patient is told not to take the medicine if they are ‘allergic (hypersensitive)’ to ingredients
or excipients in the product whereas in templates 8 and 9, the term ‘allergic’ is used alone. Of the
examined leaflets with QRD template 8 in the second download, 79.2 % had only used the term ‘allergic’
according to QRD template 8. In the third download, the percent of leaflets with QRD templates 8 and 9
which only used the term ‘allergic’ was 77.2 %.
The next heading in section 2 is ‘Take special care with X’ in QRD template 751
which was changed from
template 8 to ‘Warnings and precautions’48,49
. Of the 183 leaflets in the second download with the
template 8 contents list, 92.9 % had used the heading ‘Warnings and precautions’ and of the 359 leaflets in
the 3rd download with QRD template 8 or 9, 93.6 %. Interestingly, 3.3 % of the leaflets in the second
download had used the headings from both QRD templates 7 and 8 and 1.7 % in the third download. A
small percent of package leaflets contained a warning sentence which was neither conform to QRD
template 7 nor 8/9.
Under the heading ‘Other medicines and X’, the standard warning statements differ between QRD
template 7 and 8/9. In QRD template 7, the patient is told ‘Please tell your <doctor> <or> <pharmacist> if
you are <taking> <using> or have recently <taken> <used> any other medicines, including medicines
obtained without a prescription’51
while since QRD template 8, the sentence was altered to ‘<Tell your
<doctor> <or> <pharmacist> if you are <taking> <using>, have recently <taken> <used> or might <take>
85
<use> any other medicines48,49
. 62.3 % of the leaflets with QRD template 8 contents list in the second
download had used the statement from template 8, while 27.9 % had included the sentence from template
7. In the third download, 69.9 % of the leaflets with QRD templates 8 and 9 contents list had the statement
from template 8 or 9 while 21.4 % still retained the statement from template 7. The remaining leaflets had
a statement which was conform to neither template.
A further heading contained in QRD templates 7, 8 and 9 regards taking the named product with food and
drink and additionally the optional term ‘with alcohol’ since QRD template 8. Table 29 shows how often
each term was used in the leaflets which contained a relevant subheading. In a more detailed examination
of the leaflets in the second and third downloads where the heading ‘food and drink’ had been used, 12 %
in the second download contained information regarding drinking alcohol with the product, although this
wasn’t included in the heading, and 9.1 % in the third download. In leaflets where ‘food, drink and
alcohol’ were included, 10.5 % in the second download and 11.1 % in the third download however
contained no information regarding alcohol consumption.
Table 29: Analysis of the frequency of use of the terms food, drink and alcohol in the subheading
‘Taking X with food, drink and alcohol’ in package leaflets downloaded from the EMA website
Subheading: ‘Taking X
with….’
Percentage of leaflets using text element shown
in left column (%)
Download 2
(n = 81)
Download 3
(n = 162)
Food 1.2 0.6
Food and drink 58.1 54.9
Food, drink and alcohol 23.5 22.3
Alcohol 17.3 20.4
Drink 0 0.6
Drink and alcohol 0 1.2
Information for pregnant and breast-feeding women is also included in section 2 under the subheading
‘Pregnancy and breast-feeding’ in QRD template 7 and additionally the optional term ‘fertility’ since QRD
template 8. The majority of leaflets in the second and third download had only used the terms ‘pregnancy
and breast-feeding’ (72.7 % and 72.1%). The additional term ‘fertility’ was seen in both the second
download in 25.1 % of examined leaflets and 25.3 % in the third, although 58.7 % of these provided no
information on fertility in the second round, and 67.8 % in the third round making the term ‘fertility’
superfluous. The remaining leaflets did not provide this subheading in section 2.
86
Under the subheading for pregnancy and breast-feeding is an optional standard sentence in QRD templates
7, 8 and 9. The wording differs however between each template version, whereby QRD template 7 states
‘Ask your doctor or pharmacist for advice before taking any medicine’51
, QRD templates 8 and 9 advise
‘If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask
your <doctor> <or> <pharmacist> for advice before taking this medicine’48,49
. Table 30 shows the
frequency with which each statement was used for leaflets containing a relevant subheading.
Table 30: Analysis of the pregnancy and breast-feeding advice sentence contained in package
leaflets downloaded from the EMA website
Sentence from template version Percentage of package leaflets containing
pregnancy and breast-feeding advice sentence
shown in the left column (%)
Download 2 (n = 183) Download 3 (n = 359)
QRD template 7 conform 20.8 17.0
QRD template 8/9 conform 41.5 44.8
Neither template conform 35.5 35.4
Sentences from QRD templates 7 and 8/9 2.2 2.8
The final sentence in section 2 should be to advise patients on certain excipients in the case that they are
contained in the product according to the Excipients guideline94
. In QRD template 7, the subheading
‘Important information about some of the ingredients of X’ is used while since QRD template 8, the
patient is told ‘X contains {name the excipient(s)}’48,49, 51
. Of the leaflets identified to have used elements
from QRD templates 8/9, 60.0 % from download 2 and 63.2 % from the third download contained an
excipient which had to be mentioned in the package leaflet. The heading since template 8 was used in the
majority of these leaflets in both downloads where an excipient was contained (download 2: 87.7 %, n =
106; download 3: 91.2 %, n = 207).
4.6.7 Presentation of the list of local representatives of the marketing authorisation holder
The list of local representatives of the marketing authorisation holder must not necessarily be included at
the end of the package leaflet, but when it is present, addresses must be included for all 29 listed countries
(increased to 30 in version 948
). Astoundingly, although inclusion of this list greatly increases the length of
the leaflet, it was present in 82.3 % to 85.8 % of the investigated package leaflets (table 26) where it
accounted for up to 33.6 % of the text. On average the MAH list contributed to approximately 12.4 % to
13.0 % of the text volume when it was present.
87
QRD templates 7, 8 and 9 recommend a structure for the information regarding the MAH, for example:
United Kingdom
{Name}
<{Address}
{Town} {Postal code} – UK>
Tel: + {Telephone number}
<{e-mail}>
Following the bracketing convention therefore means that name of the MAH representative and telephone
number are the minimal information required. An email address is optional and postal address can be
added, space permitting. For each package leaflet it was noted which of these elements were present (table
31). In most cases, only the country name and name and telephone number of the local representative was
included. Only 2.6 % of the examined leaflets in the first download and third downloads contained the
maximum number of address fields and 2.7 % in the second download.
In order to save space, QRD template 7, 8 and 9 suggest listing the local representatives sequentially
rather than in a tabulated format. A detailed analysis of the MAH representative lists in the first download
showed that only two leaflets contained a sequential list while nine leaflets actually included the
information in a table with lines. The guidance in the template also states that ‘where the same
representative is designated for more than one country, the representative’s details may be listed only once
below the names of the countries concerned’48,49
. In one case in the first download, the MAH had just
included one address in this section and listed no countries, while another had abreviated the country
names to just two initials per country. One address was valid in this case for 24 countries which greatly
reduced the text volume of this section. Only five leaflets in the first download listed one address under
more than one country name.
88
Table 31: MAH information presented in package leaflets downloaded from the EMA website which
contained a MAH representative list
Information present in additional to country
name or two letter country code
Percentage of package leaflets downloaded from
the EMA website with a MAH representative list
and the text elements in the left column (%)
Download 1
(n = 465)
Download 2
(n = 476)
Download 3
(n = 454)
Name and telephone number only 70.8 71.4 71.9
Name, address and telephone number 12.3 9.5 7.0
Name, address, telephone number and email
address
2.6 2.7 2.6
Name, telephone number and email address 13.8 15.3 16.5
No clear system (mixture of names, addresses,
telephone number and emails)
0.7 1.0 2.0
4.7 Readability test of the QRD template version 8, its predecessor and a model template
4.7.1 Results of the pilot readability test
Eight people took part in the pilot round of the readability test whereby four people read the short version
of the package leaflets and four people the long BfArM version. Table 32 provides an overview of the
demographic data of the participants involved in the pilot readability test.
Table 32: Demographic data of the participants who took part in the pilot readability test
Participant
No.
Age Gender Education
level
Native
language
Medicines
taken per
day
Leaflet version read
1 33 female university German 1 short German
2 30 male university English 0 short German
3 65 male university English 2 short English
4 64 female 10th
class English 0 short English
5 39 male university German 0 long BfArM German
6 32 female university German 0 long BfArM German
7 58 female university German 5 - 7 long BfArM German
8 39 male university German 0 long BfArM German
89
The analysis of the questionnaires returned from the pilot test showed that as some of the wording differs
in the package leaflets based on the BfArM sample text as compared to the short text version, that
alternative answers could be considered as correct for certain questions. This was the case for questions 5
and 25 regarding the starting dose and breast-feeding respectively. The starting dose was given in
milligrams enalapril for package leaflets based on the BfArM sample text and in amount of tablets for
short texts. This question tests the comprehensibility of medicine specific information rather than the
template and both answers were therefore considered correct. The BfArM sample text allows Enal to be
used when feeding older nurslings while the short text contraindicates the use during breast-feeding. Here,
both answers were therefore also considered correct depending on the leaflet which had been read. In the
pilot test, the question ‘What should you do if you notice the side effect ‘liver inflammation’? was
included in the pilot test. This had caused confusion in many participants as liver problems are mentioned
in the side effect section and also elsewhere in each package leaflet. The requested side effect was
therefore changed to ‘runny nose’ as this was only provided in the side effect section.
4.7.2 Description of the demographic data of involved participants
In Germany, 194 people were initially given a package leaflet and questionnaire to complete, of which
177 were returned in the first round of the readability test (return rate 91.2%). Five participants had to
be subsequently excluded from the data set of the first test round as they were chemists, nurses or a
pharmacy assistant which resulted in a total of 172 people taking part in the first round of the
readability test in Germany. In the second round of the readability test, 171 people took part of those in
the first round, and 167 in the third round. In England, 83 people were initially given a package leaflet
and questionnaire to fill in. 69 people returned the completed questionnaire in the first round of the
readability test (83.1 % return rate), 65 in the second round and 63 in the third round.
Table 33: Age range of the participants at the time of the first round of the readability test
Age range
(years)
Percentage of participants with the age range shown in the left column (%)
England short package
leaflet
(n = 69)
Germany short
package leaflet
(n = 76)
Germany long BfArM
package leaflet
(n = 96)
≤ 19 0 6.6 36.5
≥ 20 - ≤ 39 32.3 27.6 13.5
≥ 40 - ≤ 59 17.6 59.2 42.7
≥ 60 years
and older
50.0 6.6 7.3
90
At the time of the first round of the readability test, the age of the participants in Germany ranged
between 16 and 78 for the short text version (average age 42.2 years) and between 14 and 79 for the
BfArM text version (average age 36.4 years). In England the age of the participants ranged from 24 to
79 (average age 52 years) (table 33). More females than males took part in the test in both countries
(Germany short text version: 57.9 % females, Germany BfArM text version: 61.5 % females; England:
64.7 % females). In Germany 26.2 % of the participants lived in Lichtenfels and 53.1 % in the
surrounding area (postcode 96***). In England, participants place of residence were more widely
spread. The highest number lived in the Cambridge region (49.3 %, n = 34), while most of the
remaining came from the Norwich, Hereford or Manchester areas.
All levels of education were represented in both subject groups (table 34), although in England
participants with a university degree were clearly in the majority (66.8 %). The most common ‘last
practiced occupation’ was school child (22.1 %, n = 38) and teacher (n = 16, 9.3 %) in Germany and
teacher in England (13.2 %, n = 9). The average number of university years attended of participants
with this education level in England was 3.8 and in Germany 4.6.
Table 34: Education level of the participants involved in the readability test
Education
level
Percentage of participants with the education level shown in the left column
(%)
England short package
leaflet
(n = 69)
Germany short
package leaflet
(n = 76)
Germany long BfArM
package leaflet
(n = 96)
8th
class 0 9.2 43.7
10th
class 7.2 35.5 12.5
A-levels 10.1 11.8 10.4
Polytechnic
college
7.2 5.3 8.3
University 66.8 14.5 18.8
Other 8.7 23.7 6.3
The majority of participants took no medication during the first readability test round in both
countries (table 35), although in England more medication was used probably as the participants
involved were older than those in Germany. When examining the types of medicine taken of the
participants who had read the short package leaflet versions, 10 of the 76 people (13.2 %) in
91
Germany used a medicine to treat high blood pressure and 12 of the 69 participants (17.4 %) in
England. Of the 96 participants who had read the long BfArM version of the package leaflet in
Germany, 18 took a medicine to treat high blood pressure (18.8 %).
Table 35: Number of medicines taken by day by participants at the time of the first round of the
readability test
Medicines
used per day
Percentage of participants who took the number of medicines shown in the
left column (%)
England short package
leaflet
(n = 69)
Germany short
package leaflet
(n = 76)
Germany long BfArM
package leaflet
(n = 96)
0 39.1 65.7 59.4
1 31.9 22.4 25.0
2 17.4 5.3 8.3
3 - 4 7.3 5.3 6.3
5 - 7 2.9 1.3 0
8 - 10 1.4 0 1.0
Table 36: How long participants read a day, and read, heard or saw medical reports in an average
week at the time of the first readability test round
How long participants read a day (percentage of participants (%))
Hours England short package
leaflet
(n = 69)
Germany short
package leaflet
(n = 76)
Germany long BfArM
package leaflet
(n = 96)
0 - < 1 7.2 30.3 34.4
≥ 1 - < 2 43.5 55.3 36.5
≥ 2 - < 3 33.3 11.8 20.8
≥ 3 15.9 2.6 8.3
In an average week, how long participants read, heard or saw medical reports
(percentage of participants (%))
0 - < 1 50.7 53.9 67.7
≥ 1 - < 2 36.2 27.6 19.8
≥ 2 - < 3 4.3 13.2 10.4
≥ 3 8.7 5.3 2.1
92
The majority of participants in the readability test in both countries read between 1 and 2 hours a
day (table 36). Over 50% read, heard or saw medical reports for up to 1 hour per week.
4.7.3 Analysis of the time taken to answer, locatability and comprehensibility of 26 requested
contents
Participants who had read leaflets with QRD template 7.3.1 needed the longest time to answer the
questions for all text versions regardless of country and text length (table 37). There was no significant
difference in the time needed to complete the questions in Germany or England for the short text versions.
However, a significant difference was found for the longer text versions in Germany between the model
template and QRD template 7.3.1 (p = 0.008) and the model template and QRD template 8 (p = 0.003).
Table 37: Time in minutes taken by the participants to answer 26 content questions and number of
words contained in each package leaflet
Package leaflet No.
words
Time to answer the 26 content questions
(minutes)
Calculated
median min. max. n
EN-Model-template-short text 1221 17.8 7 35 66
EN-QRD-template-7.3.1-short text 2169 19.7 9 50 62
EN-QRD-template-8-short text 2227 19.3 10 40 64
DE-Model-template-short text 1007 20.7 10 60 71
DE-QRD-template-7.3.1-short text 2002 23.4 10 60 69
DE-QRD-template-8-short text 2023 20.3 10 60 70
DE-Model-template-BfArM text 2893 24.5 5 70 92
DE-QRD-template-7.3.1-BfArM text 3890 29.2 6 90 90
DE-QRD-template-8-BfArM text 3956 28.6 10 120 93
EN = English, DE = German, n = number of participants, min. = minimum, max. = maximum. Some
people forgot to note the starting and finishing time to answer the 26 content questions. Therefore ‘n’
of the locatability time is lower than the ‘n’ for the correct, wrong and not found answers.
Participants provided the highest percent of correct answers for the short text versions with the model
template, followed by QRD template 8 in both countries (table 38). There were significant differences
found for the number of correct answers provided between each leaflet version in a group (p ≤ 0.026)
except for the long BfArM text version between the model template and QRD template 8 (appendix 13).
93
The most wrong answers were provided when package leaflets with QRD template 7.3.1 had been read.
This result was not affected either by language or the length of the leaflet. There were significant
differences found between all leaflet versions for the number of wrong answers provided (p ≤ 0.001). In
Germany, participants gave significantly more not found answers with the model template in comparison
to QRD template version 7.3.1 for short package leaflet versions (p = 0.006). For the long package leaflet
versions there were significant differences in the number of not found answers between the model
template and both QRD templates (p < 0.001, appendix 13).
94
Table 38: Calculated median percentage and minimum (min.) and maximum (max.) percentage of correct, wrong and not found answers itemised for
each package leaflet
Package leaflet
Percentage correct answers (%) Percentage wrong answers (%) Percentage not found
answers (%)
n Calculated
median min. max.
Calculated
median min. max.
Calculated
median min. max.
EN-Model-template-short text 95.0 69.0 100 1.3 0 8.0 3.6 0 27.0 67
EN-QRD-template-7.3.1-short text 83.4 69.0 96.0 11.6 0 23.0 3.4 0 27.0 65
EN-QRD-template-8-short text 91.5 73.0 100 5.2 0 15.0 3.0 0 19.0 65
DE-Model-template-short text 93.2 46.2 100 2.2 0 19.2 4.4 0 46.2 75
DE-QRD-template-7.3.1-short text 87.3 50.0 100 9.7 0 26.9 2.7 0 38.5 72
DE-QRD-template-8-short text 91.1 50.0 100 5.0 0 15.4 3.3 0 42.3 73
DE-Model-template-BfArM text 80.4 38.5 96.2 7.7 0 23.1 11.1 0 46.2 93
DE-QRD-template-7.3.1-BfArM text 76.2 34.6 96.2 15.0 3.9 42.3 7.6 0 42.3 93
DE-QRD-template-8-BfArM text 81.2 34.6 100 11.5 0 38.5 6.5 0 38.5 94
EN = English, DE = German, n = number of participants
95
4.7.4 Analysis of locatability and comprehensibility of QRD template texts intended at the start
of the package leaflet
Both QRD template versions 7.3.1 and 8 start with an information box. For the readability test, the active
ingredient enalapril had been chosen and therefore the information box for prescription only medicines
was investigated. The information that the medicine has been ‘prescribed for you’, is included in the
information box of QRD templates 7.3.1 and 8. This statement was found in section 5 of leaflets using the
model template which did not have an information box in order to reduce text volume. It stated there:
‘Enal is prescribed only for you’. Participants were asked to identify whether the medicine is available on
prescription. Short and long versions of the leaflets with QRD templates 7.3.1 or 8 showed more correct
answers than those with the model template although these differences were not significant (table 39). The
participants provided significantly more not found answers when using the model template and the
German short text version compared to the QRD template 7.3.1 and QRD template 8 (p ≤ 0.035, appendix
21). For all other leaflet versions, no significant differences were found in the number of wrong or not
found answers between the information relating to the prescription status.
Table 39: Percent correct, wrong and not found answers for each package leaflet for the question ‘Is
this medicine available with or without prescription by a doctor?’
Package leaflet
Is this medicine available with or without
prescription by a doctor?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 80.6 1.5 17.9 67
EN-QRD-template-7.3.1-short text 87.7 1.5 10.8 65
EN-QRD-template-8-short text 87.7 4.6 7.7 65
DE-Model-template-short text 65.3 1.3 33.3 75
DE-QRD-template-7.3.1-short text 80.6 5.6 13.9 72
DE-QRD-template-8-short text 76.7 4.1 19.2 73
DE-Model-template-BfArM text 79.6 1.1 19.4 93
DE-QRD-template-7.3.1-BfArM text 82.8 5.4 11.8 93
DE-QRD-template-8-BfArM text 83.0 3.2 13.8 94
EN = English, DE = German, n = number of participants
96
When a medicine has been prescribed for a patient by a doctor, then it should only be used by them and
not given to others, even if it appears that they have similar symptoms. For QRD templates 7.3.1 and 8,
the instruction not to pass the prescription medicine on to others is contained in the information box at the
start of the leaflet. In the model template, a statement is included regarding this point in section 5. For
none of the tested leaflets could a clear disadvantage be identified regarding answering this question and
no significant differences between template versions were identified (table 40).
Table 40: Percent correct, wrong and not found answers for each package leaflet for the question
‘Should you give Enal to other people to use with a similar illness?’
Package leaflet
Should you give Enal to other people to use
with a similar illness?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 97.0 0 3.0 67
EN-QRD-template-7.3.1-short text 98.5 0 1.5 65
EN-QRD-template-8-short text 95.4 0 4.6 65
DE-Model-template-short text 94.7 0 5.3 75
DE-QRD-template-7.3.1-short text 97.2 0 2.8 72
DE-QRD-template-8-short text 97.3 0 2.7 73
DE-Model-template-BfArM text 94.6 1.1 4.3 93
DE-QRD-template-7.3.1-BfArM text 90.3 3.2 6.5 93
DE-QRD-template-8-BfArM text 98.9 0 1.1 94
EN = English, DE = German, n = number of participants
4.7.5 Analysis of comprehensibility and ease of location of information in section 1 of the
package leaflet
The indication for a particular medicine was always contained in section 1 of the leaflet regardless of
which template had been used. Leaflets with the model template provided the largest percentage of correct
answers regardless of whether the text was long or short (table 41). However, this difference was not
significant. Also, no significant differences in the number of wrong or not found answers were found
between leaflet versions.
97
Table 41: Percent correct, wrong and not found answers for each package leaflet for the question
‘What is Enal used to treat?’
Package leaflet
What is Enal used to treat?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 95.4 4.6 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 100 0 0 75
DE-QRD-template-7.3.1-short text 95.8 4.2 0 72
DE-QRD-template-8-short text 98.6 1.4 0 73
DE-Model-template-BfArM text 98.9 1.1 0 93
DE-QRD-template-7.3.1-BfArM text 94.6 3.2 2.2 93
DE-QRD-template-8-BfArM text 92.6 7.4 0 94
EN = English, DE = German, n = number of participants
4.7.6 Analysis of comprehensibility and ease of location of information in section 2 of the package
leaflet
Section 2 of the package leaflet is the most lengthy and contains a wide range of information ranging from
contraindications, interactions, to warnings and precautions. Questions relating to all aspects contained in
section 2 were included in the readability test.
Correctly understanding contraindications is of special importance for safe use of any medicine for all
users. Women who are pregnant or breast-feeding are a special patient group where it is vital that
information can be correctly located as incorrect use could potentially damage the growing foetus,
pregnant women or feeding child. Information for pregnant or breast-feeding women was included under a
relevant subheading in section 2 of leaflets with QRD templates 7.3.1 and 8. Pregnancy is also a
contraindication for the substance enalapril, and was therefore additionally provided in the
contraindication section at the start of section 2 in these template versions. The model template used no
separate heading/subsection or general sentence as recommended in the QRD template but details are
found in the contraindication section. The BfArM text versions provided additional information relating to
pregnancy and breast-feeding in the warnings and precautions section of all investigated template
versions. Whether pregnant women can use Enal was answered over 96 % correctly for all versions of the
98
leaflet (table 42). There were no significant differences between template versions for the number of
correct answers, wrong answers or not found answers.
Table 42: Percent correct, wrong and not found answers for each package leaflet for the question
‘Should women who think they might be pregnant use this medicine?’
Package leaflet
Should women who think they might be
pregnant use this medicine?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 98.5 0 1.5 67
EN-QRD-template-7.3.1-short text 96.9 0 3.1 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 98.7 0 1.3 75
DE-QRD-template-7.3.1-short text 98.6 0 1.4 72
DE-QRD-template-8-short text 100 0 0 73
DE-Model-template-BfArM text 100 0 0 93
DE-QRD-template-7.3.1-BfArM text 98.9 0 1.1 93
DE-QRD-template-8-BfArM text 98.9 1.1 0 94
EN = English, DE = German, n = number of participants
The question ‘Under what circumstances may breast-feeding women take Enal?’ was answered most
correctly for the short text versions (table 43). No significant differences were found for the number of
correct answers or not found answers between any template versions in either country when using the
English or German short package leaflet text.
Use of the BfArM text was shown to cause difficulties in finding and understanding information relating
to breast-feeding. This situation which was most pronounced when QRD template 7.3.1 was used although
no significant differences were found between template versions for the number of wrong answers.
99
Table 43: Percent correct, wrong and not found answers for each package leaflet for the question
‘Under what circumstances may breast-feeding women take Enal?’
Package leaflet
Under what circumstances may breast-
feeding women take Enal?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 95.5 0 4.5 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 97.3 0 2.7 75
DE-QRD-template-7.3.1-short text 97.2 0 2.8 72
DE-QRD-template-8-short text 98.6 0 1.4 73
DE-Model-template-BfArM text 87.1 4.3 8.6 93
DE-QRD-template-7.3.1-BfArM text 76.3 10.8 12.9 93
DE-QRD-template-8-BfArM text 87.2 2.1 10.6 94
EN = English, DE = German, n = number of participants
The question ‘Can you take this medicine if you are allergic to lactose?’ was where the participants
provided the fewest correct answers in the readability test (table 44). Whereas QRD template versions 7.3.1
and 8 contain an extra subheading in section 2 stating that the product contains lactose, the model template
only lists lactose in the list of ingredients at the end of the leaflet. Many participants understood the wording
in the leaflets using the QRD templates 7.3.1 and 8 to mean that they could take Enal providing they had
contacted a doctor first and not that they shouldn’t if they are allergic to lactose. Although the model
template had no extra subheading for lactose, it still produced the largest number of correct answers for the
short text leaflet versions in both languages. This difference was significant in England only between the
model template and QRD template 8 (p = 0.015, appendix 14). No significant difference in correct answers
was found between templates for the long or short German text versions.
The question regarding taking the medicine when an allergy to lactose is known, was usually answered
more frequently wrongly with leaflets with QRD template 7.3.1 or 8 and ‘not found’ with leaflets with the
model template. The difference was significant in the number of wrong and not found answers between the
model template and QRD template 7.3.1 and the model template and QRD template 8 (p ≤ 0.035) for the
short text versions in both countries (appendices 17, 18, 20 and 21). There was also a significant difference
100
for the long BfArM text in the number of wrong answers between the model template and QRD template 8
(p < 0.001, appendix 19), and not found answers between the model template and QRD template 7.3.1 and
the model template and QRD template 8 (p < 0.001, appendix 23). There was no significant difference in
the number of not found or wrong answers between long or short text versions between QRD template 7.3.1
and 8.
Table 44: Percent correct, wrong and not found answers for each package leaflet for the question
‘Can you take this medicine if you are allergic to lactose?’
Package leaflet
Can you take this medicine if you are allergic
to lactose?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 41.8 10.4 47.8 67
EN-QRD-template-7.3.1-short text 33.8 60.0 6.2 65
EN-QRD-template-8-short text 20.0 75.4 4.6 65
DE-Model-template-short text 38.7 20.0 41.3 75
DE-QRD-template-7.3.1-short text 29.2 61.1 9.7 72
DE-QRD-template-8-short text 30.1 68.5 1.4 73
DE-Model-template-BfArM text 35.5 20.4 44.1 93
DE-QRD-template-7.3.1-BfArM text 36.6 50.5 12.9 93
DE-QRD-template-8-BfArM text 37.2 57.4 5.3 94
EN = English, DE = German, n = number of participants
Section 2 of the tested Enal package leaflet contains warnings and precautions for patients which are
applicable under certain situations i.e. when driving and operating machinery or if patients have to undergo
an operation. Therefore it was investigated whether users can locate and understand this information. A
separate subheading for ‘Driving and using machines’ was included in section 2 of all template versions.
Although most of the participants had located the explanatory statement that ‘reaction time may be affected’
under the specified subheading, others had read the list of side effects and drawn their own conclusions that
adverse effects such as ‘tiredness’ or ‘dizziness’ listed in section 4 would also affect the ability to drive and
use machines. Common answers provided from leaflets with the BfArM text were that subjects had simply
written ‘start of treatment’ or ‘dose increase’ which did not answer the question but were explanations
contained in the section regarding driving and using machines. In England, 100 % of the subjects could
101
locate and provide at least one reason why their ability to drive could be affected regardless of the used
template version (table 45). No significant differences were found between template versions used in
Germany for the long BfArM and short package leaflet texts in the number of correct answers, wrong
answers or not found answers.
Table 45: Percent correct, wrong and not found answers for each package leaflet for the question
‘Write down one reason why your ability to drive may be reduced due to taking Enal.’
Package leaflet
Write down one reason why your ability to
drive may be reduced due to taking Enal.
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 96.0 1.3 2.7 75
DE-QRD-template-7.3.1-short text 98.6 0 1.4 72
DE-QRD-template-8-short text 95.9 0 4.1 73
DE-Model-template-BfArM text 79.6 16.1 4.3 93
DE-QRD-template-7.3.1-BfArM text 76.3 17.2 6.5 93
DE-QRD-template-8-BfArM text 84.0 9.6 6.4 94
EN = English, DE = German, n = number of participants
Warnings and precautions are recommended for the substance enalapril if patients must undergo any
operations including those at the dentist. Therefore participants were asked to provide information on what
they should do if they have to undergo a dental operation. The most correct answers were provided by
participants using the model template independent of language or whether the text version was long or
short (table 46). The differences in correct answers provided between the model template and both QRD
template versions with short text in England were significant as well as between leaflets with QRD
template 7.3.1 and 8 (p ≤ 0.002, appendix 14). For the short text version in Germany, significant
differences in the number of correct answers were found between the model template and QRD template
7.3.1 and QRD template 7.3.1 compared to QRD template 8 only (p < 0.001, appendix 15). However, no
significant difference in the number of correct answers was found between the templates used with the
BfArM text.
102
Participants who had read the short text version and QRD template 7.3.1 had the greatest problems in
correctly answering or locating the information in the short text package leaflets, where this information
was presented in a bullet point below the subheading ‘Take special care with Enal’. In the longer BfArM
text version with template 7.3.1, a sentence was included that the user should inform their dentist before
an operation using the same ‘Take special care with...’ subheading. For QRD template 8, the mandatory
statement ‘Talk to your doctor, pharmacist or nurse before taking Enal’ is presented under the subheading
‘Warnings and precautions’. The most common incorrect answer given for package leaflets with QRD
template 7.3.1 was that participants had simply answered that ‘special care’ should be taken if they need
dental treatment. This accounted for 93.9 % of the wrong answers in England and 73.1 % in Germany. A
significant difference was found for the short text versions between the number of wrong answers
provided with the model template compared to leaflets with QRD template 7.3.1 or the leaflets with QRD
template 7.3.1 compared to QRD template 8 (p < 0.001, appendices 17 and 18). No significant difference
in the number of wrong answers was found between the templates used with the BfArM text. A significant
difference was only found in the number of not found answers between the model template and QRD
template 8 in England (p = 0.002, appendix 20) and the short text with the model template and QRD
template 7.3.1 in Germany (p = 0.016, appendix 21).
Table 46: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do if you need a dental operation while taking Enal?’
Package leaflet
What should you do if you need a dental
operation while taking Enal?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 91.0 0 9.0 67
EN-QRD-template-7.3.1-short text 12.3 70.8 16.9 65
EN-QRD-template-8-short text 72.3 0 27.7 65
DE-Model-template-short text 97.3 1.3 1.3 75
DE-QRD-template-7.3.1-short text 48.6 40.3 11.1 72
DE-QRD-template-8-short text 89.0 2.7 8.2 73
DE-Model-template-BfArM text 88.2 1.1 10.8 93
DE-QRD-template-7.3.1-BfArM text 80.6 3.2 16.1 93
DE-QRD-template-8-BfArM text 81.9 2.1 16.0 94
EN = English, DE = German, n = number of participants
103
It is of importance that patients inform their doctor if they have just had a kidney transplant before taking
the substance enalapril. This precautionary instruction was provided in the short and BfArM package
leaflets in a bullet point contained within a list of several other bullet points. To test whether the correct
action would be taken by a patient who had had a kidney transplant, a corresponding question was
included. Again, the most correct answers were provided by the model template regardless of the length of
the package leaflet followed by leaflets with QRD template 8 (table 47). The difference in the number of
correct answers provided was significant between the model template and QRD template 7.3.1 and QRD
template 7.3.1 and 8 (p < 0.001) for all text versions regardless of country and length (appendices 14, 15
and 16). There were no significant differences in the number of correct answers provided between leaflets
with the model template and QRD template 8.
Participants who had received leaflets with QRD template 7.3.1 gave more wrong than correct answers.
The most common wrong answer provided to this question was again ‘take special care’ without any
specific action which accounted for 100 % of the wrong answers in England and 87.5 % in Germany.
Significant differences in the number of wrong answers were found for the short text versions between the
model template and QRD template 7.3.1 and between leaflets with QRD template 7.3.1 and QRD template
8 (p < 0.001, appendices 17 and 18). For the long BfArM text versions, significant differences in the
number of wrong answers were found between all template versions (p ≤ 0.031, appendix 19).
Significant differences in the number of not located answers were identified between the model template
and QRD template 7.3.1 and the model template and QRD template 8 in England (both p = 0.021,
appendix 20). For the long BfArM text versions in Germany, the number of not found answers was
significantly different between the model template and QRD template 8 and the QRD template 7.3.1 and
QRD template 8 (both p = 0.035, appendix 22). No significant differences in the number of not found
answers were found between template versions for the short text versions in Germany.
104
Table 47: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do if you have just had a kidney transplant and you need Enal?’
Package leaflet
What should you do if you have just had a
kidney transplant and you need Enal?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 92.5 6.0 1.5 67
EN-QRD-template-7.3.1-short text 10.8 75.4 13.8 65
EN-QRD-template-8-short text 84.6 3.1 12.3 65
DE-Model-template-short text 93.3 1.3 5.3 75
DE-QRD-template-7.3.1-short text 31.9 59.7 8.3 72
DE-QRD-template-8-short text 89.0 4.1 6.8 73
DE-Model-template-BfArM text 77.4 7.5 15.1 93
DE-QRD-template-7.3.1-BfArM text 31.2 54.8 14.0 93
DE-QRD-template-8-BfArM text 73.4 22.3 4.3 94
EN = English, DE = German, n = number of participants
Interactions between medicines already being taken and those newly prescribed must be taken into
consideration to ensure safe use of any medicine. Therefore, participants were asked to locate an
example medicine which was listed in the package leaflet for treating heart rhythm disorders which
causes interactions with Enal. All short text versions included the answer to this question under the
subheading ‘Taking other medicines’ (model template and QRD template 7.3.1 and ‘Other medicines
and Enal’ (QRD template 8), while the three BfArM package leaflets presented this information in the
section ‘Take special care’/’Warnings and precautions’ section rather than the sections where
interactions with other medicines were described. There were no significant differences in the number
of correct answers, wrong answers or not found answers given by the participants between the three
template versions of each group, although for the short text versions QRD template 7.3.1 provided the
most not found answers (table 48).
105
Table 48: Percent correct, wrong and not found answers for each package leaflet for the question
‘Name one medicine that is used to treat heart rhythm disorders which can influence Enal.’
Package leaflet
Name one medicine that is used to treat heart
rhythm disorders which can influence Enal.
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 92.5 1.5 6.0 67
EN-QRD-template-7.3.1-short text 84.6 0 15.4 65
EN-QRD-template-8-short text 89.2 3.1 7.7 65
DE-Model-template-short text 86.7 5.3 8.0 75
DE-QRD-template-7.3.1-short text 84.7 2.8 12.5 72
DE-QRD-template-8-short text 93.2 1.4 5.5 73
DE-Model-template-BfArM text 28.0 20.4 51.6 93
DE-QRD-template-7.3.1-BfArM text 35.5 23.7 40.9 93
DE-QRD-template-8-BfArM text 30.9 26.6 42.6 94
EN = English, DE = German, n = number of participants
It was also investigated whether participants could find what they should do if they were already taking a
medicine to reduce blood sugar levels before taking Enal, namely inform their doctor (table 49). This
information was contained in every leaflet version in section 2 under a subheading regarding interactions.
All text versions with the model template produced the most correct answers although this was not
significant in either country. No significant differences were found in the number of wrong answers or not
found answers in England or Germany.
106
Table 49: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do if you already take medicines to reduce blood sugar levels and also need
Enal?’
Package leaflet
What should you do if you already take
medicines to reduce blood sugar levels and
also need Enal?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 98.5 0 1.5 67
EN-QRD-template-7.3.1-short text 87.7 6.2 6.2 65
EN-QRD-template-8-short text 98.5 0 1.5 65
DE-Model-template-short text 93.3 1.3 5.3 75
DE-QRD-template-7.3.1-short text 93.1 0 6.9 72
DE-QRD-template-8-short text 91.8 0 8.2 73
DE-Model-template-BfArM text 76.3 6.5 17.2 93
DE-QRD-template-7.3.1-BfArM text 68.8 20.4 10.8 93
DE-QRD-template-8-BfArM text 71.3 19.1 9.6 94
EN = English, DE = German, n = number of participants
The effects of drinking alcohol when taking medicines are often unpredictable or lead to increased
adverse reactions. Patients should therefore be able to easily locate this information. Package leaflets
with the model leaflet and QRD template 7.3.1 contained information on taking the medicine with
alcohol under the headings ‘Food and drink’ and ‘Taking Enal with food and drink’ respectively while
leaflets with QRD template 8 used the heading ‘Enal with food, drink and alcohol’. A common answer
which was given when the long BfArM text had been read was that participants simply copied what
was written in the leaflet i.e. that alcohol can increase the blood pressure lowering effect of ACE-
inhibitors. Although this response is not incorrect in itself, it was considered to be as a wrong answer
as participants didn’t come to the conclusion relating to the correct action that alcohol should be
avoided. This led to the large number of wrong answers for the three BfArM package leaflet versions
(table 50). No significant differences were found between the template versions of each group in the
number of correct answers. A significant difference was found between the number of not found
answers between the QRD template 7.3.1 and QRD template 8 on the case of the long BfArM text
(p = 0.008, appendix 23). There were no significant differences in the number of wrong answers
between any template versions.
107
Table 50: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do with regard to drinking alcohol when taking this medicine?’
Package leaflet
What should you do with regard to drinking
alcohol when taking this medicine?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 98.7 1.3 0 75
DE-QRD-template-7.3.1-short text 98.6 0 1.4 72
DE-QRD-template-8-short text 98.6 0 1.4 73
DE-Model-template-BfArM text 54.8 39.8 5.4 93
DE-QRD-template-7.3.1-BfArM text 55.9 34.4 9.7 93
DE-QRD-template-8-BfArM text 59.6 39.4 1.1 94
EN = English, DE = German, n = number of participants
Table 51: Percent correct, wrong and not found answers for each package leaflet for the question
‘What is Enal used for treating in children?’
Package leaflet
What is Enal used for treating in children?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 100 0 0 75
DE-QRD-template-7.3.1-short text 95.8 1.4 2.8 72
DE-QRD-template-8-short text 97.3 0 2.7 73
DE-Model-template-BfArM text 95.7 0 4.3 93
DE-QRD-template-7.3.1-BfArM text 96.8 0 3.2 93
DE-QRD-template-8-BfArM text 91.5 3.2 5.3 94
EN = English, DE = German, n = number of participants
108
Information regarding what Enal can be used for treating in children was contained in section 3 ‘How to
take Enal’ in the short text versions. The longer BfArM text versions had this information in sections 2
(‘Warnings and precautions’) and 3 (‘How to take Enal’). For leaflets with the model template and short
text, 100% of subjects located and provided the correct answer in Germany and England, which also
applied to the two other leaflets tested in England (table 51). No significant differences were found for the
number of correct answers, wrong answers or not found answers between the three template versions in
each package leaflet group.
4.7.7 Analysis of comprehensibility and ease of location information in section 3 of the package
leaflet
Participants were asked to provide the starting dose of Enal to treat high blood pressure in adults
(table 52). For the short text versions the starting dose was provided in ‘number of tablets’ while for the
long BfArM text version the milligrams of active ingredient were noted which corresponded to the manner
in which the starting dose was described in the particular leaflet versions. There were no significant
differences in the number of correct answers found between the three template versions when the number
of tablets was noted rather than milligrams. However, there was a significant difference in the number of
not found answers in leaflets with the long BfArM text between the model template and QRD template
7.3.1 (p = 0.022) and the QRD template 7.3.1 and QRD template 8 (p < 0.001, appendix 22). There is no
obvious explanation for the large number of not found answers for the BfArM text and QRD template
7.3.1. There were no significant differences found between the number of wrong answers provided with
any template version.
Accidentally forgetting to take a dose of medicine is a possible occurrence which causes patients to be
uncertain as to how they should act - should they take a double dose to make up for the forgotten dose?
Participants provided the greatest number of correct answers for all leaflets tested using the model
template but this difference was not significant (table 53). Also, no significant differences were found in
the number of wrong or not found answers between the three template versions.
109
Table 52: Percent correct, wrong and not found answers for each package leaflet for the question
‘What is the starting dose of Enal to treat high blood pressure in adults?’
Package leaflet
What is the starting dose of Enal to treat high
blood pressure in adults?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 98.5 0 1.5 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 98.7 1.3 0 75
DE-QRD-template-7.3.1-short text 97.2 2.8 0 72
DE-QRD-template-8-short text 97.3 2.7 0 73
DE-Model-template-BfArM text 90.3 7.5 2.2 93
DE-QRD-template-7.3.1-BfArM text 80.6 6.5 12.9 93
DE-QRD-template-8-BfArM text 87.2 12.8 0 94
EN = English, DE = German, n = number of participants
Table 53: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do if you forget to take a dose of this medicine?’
Package leaflet
What should you do if you forget to take a
dose of this medicine? (%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 93.8 3.1 3.1 65
EN-QRD-template-8-short text 96.9 3.1 0 65
DE-Model-template-short text 98.7 1.3 0 75
DE-QRD-template-7.3.1-short text 97.2 2.8 0 72
DE-QRD-template-8-short text 94.5 4.1 1.4 73
DE-Model-template-BfArM text 94.6 4.3 1.1 93
DE-QRD-template-7.3.1-BfArM text 87.1 10.8 2.2 93
DE-QRD-template-8-BfArM text 86.2 10.6 3.2 94
EN = English, DE = German, n = number of participants
110
Taking too much of a medicine can lead to overdose, therefore patients should swiftly be able to locate
relevant information on how they should act. This question was answered correctly in all cases in England
and for the long text version with QRD template 8 in Germany (table 54). There were no significant
differences between template versions in the number of correct and wrong answers given including not
located information.
Table 54: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do if you have taken too much Enal?’
Package leaflet
What should you do if you have taken too
much Enal? (%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 97.3 2.7 0 75
DE-QRD-template-7.3.1-short text 91.7 5.6 2.8 72
DE-QRD-template-8-short text 95.9 2.7 1.4 73
DE-Model-template-BfArM text 96.8 2.2 1.1 93
DE-QRD-template-7.3.1-BfArM text 94.6 2.2 3.2 93
DE-QRD-template-8-BfArM text 100 0 0 94
EN = English, DE = German, n = number of participants
Before a patient stops taking an antihypertensive medicine, a doctor must be consulted. With QRD
template 7.3.1 some participants were of the opinion that the dose should be gradually reduced although it
is clearly stated in all versions that a doctor must be consulted. A significant difference was found in the
number of correct answers provided between QRD template 7.3.1 and QRD template 8 for the BfArM text
versions only (p = 0.035, appendix 16) (table 55). No further significant differences occurred for this
question between any template versions.
111
Table 55: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do if you want to stop taking this medicine?’
Package leaflet
What should you do if you want to stop
taking this medicine? (%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 98.5 0 1.5 67
EN-QRD-template-7.3.1-short text 95.4 0 4.6 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 98.7 0 1.3 75
DE-QRD-template-7.3.1-short text 100 0 0 72
DE-QRD-template-8-short text 97.3 0 2.7 73
DE-Model-template-BfArM text 91.4 3.2 5.4 93
DE-QRD-template-7.3.1-BfArM text 82.8 10.8 6.5 93
DE-QRD-template-8-BfArM text 92.6 6.4 1.1 94
EN = English, DE = German, n = number of participants
Furthermore, participants were asked to provide information relating to duration of use which was stated
in all leaflets to be determined by a doctor. For the long BfArM versions tested in Germany, a significant
difference in the number of correct answers (p = 0.002) and not located answers (p = 0.007) was found
between the model template and QRD template 7.3.1 only (table 56, appendices 16 and 23). No other
significant differences were found between template versions for the number of correct answers, wrong
answers or not found answers.
112
Table 56: Percent correct, wrong and not found answers for each package leaflet for the question
‘How long should Enal be used?’
Package leaflet
How long should Enal be used?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 92.5 1.5 6.0 67
EN-QRD-template-7.3.1-short text 92.3 0 7.7 65
EN-QRD-template-8-short text 90.8 1.5 7.7 65
DE-Model-template-short text 90.7 1.3 8.0 75
DE-QRD-template-7.3.1-short text 93.1 1.4 5.6 72
DE-QRD-template-8-short text 91.8 2.7 5.5 73
DE-Model-template-BfArM text 77.4 15.1 7.5 93
DE-QRD-template-7.3.1-BfArM text 57.0 23.7 19.4 93
DE-QRD-template-8-BfArM text 68.1 20.2 11.7 94
EN = English, DE = German, n = number of participants
4.7.8 Analysis of comprehensibility and ease of location of information in section 4 of the package
leaflet
The occurrence of side effects is always possible when taking any medication and therefore the
participants ease in locating a particular side effect and their frequency in package leaflets was
investigated using the side effect example ‘hair loss’. Participants provided the most correct answers in
England and in the case of the short German package leaflets when using the model template, while QRD
template 8 showed the most correct answers for the long BfArM text version (table 57). There were
significant differences in the number of correct answers found for the long BfArM text between the model
template and QRD template 8 (p = 0.031) and QRD template 7.3.1 and 8 (p = 0.006, appendix 16). For the
long BfArM text there were significant differences in the number of wrong answers between the model
template and QRD template 7.3.1 and the QRD template 7.3.1 and QRD template 8 (both p < 0.001,
appendix 19). Here, the most commonly provided wrong answer was that hair loss was ‘rare’ rather than
‘uncommon’. There were also significant differences between the number of not found answers between
the model template and QRD template 7.3.1 (p = 0.021) and the model template and QRD template 8 (p =
0.021) for the long BfArM text (appendix 22). For the short text versions there were no significant
differences in the number of correct answers, wrong answers or not found answers between template
versions.
113
Table 57: Percent correct, wrong and not found answers for each package leaflet for the question
‘How frequent is the side effect ‘hair loss’?’
Package leaflet
How frequent is the side effect ‘hair loss’?
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 98.5 1.5 0 65
EN-QRD-template-8-short text 93.8 4.6 1.5 65
DE-Model-template-short text 93.4 6.6 0 75
DE-QRD-template-7.3.1-short text 90.3 8.3 1.4 72
DE-QRD-template-8-short text 90.4 4.1 5.5 73
DE-Model-template-BfArM text 65.6 5.4 29.0 93
DE-QRD-template-7.3.1-BfArM text 63.4 20.5 16.1 93
DE-QRD-template-8-BfArM text 79.8 5.3 14.9 94
EN = English, DE = German, n = number of participants
The frequency of side effects can be misunderstood meaning that users believe a side effect occurs much
more often than it actually does183
. The location for describing the frequencies of side effects differed
between versions of the leaflet (see package leaflets attached in appendices 4 - 12). For QRD template
7.3.1, a table was used at the start of section 4, while for the model template and QRD template 8, the
frequencies were included in subheadings in the side effect list of each frequency group. The side effects
in QRD template 8 were also described according to the recommendations in the annotated template with
most serious side effects and required actions listed first followed by a list of all other side effects in order
of decreasing frequency. The terms used to describe frequencies differed between the different template
versions as follows in the case of the ‘common’ frequency:
Model template - ‘Common, affects 1 to 10 per 100 people’60,120,182
QRD template 7.3.1 - ‘Common - less than 1 in 10, but more than 1 in 100 patients’36
QRD template 8 - ‘Common: may affect up to 1 in 10 people’48,49
Participants were asked to write down in numbers the side effect frequency explanation, using the
following format: ‘ <...> of <.....> people’, relating to how many people are affected by a side effect if it is
‘rare’. The model template and QRD template 8 provided 100 % correct answers in England (table 58).
There were no significant differences in the number of correct answers, wrong answers or not found
114
answers between the three template versions although QRD template 7.3.1 package leaflets showed the
lowest number of correct answers.
Table 58: Percent correct, wrong and not found answers for each package leaflet for the question
‘How many people are affected by a side effect if it is ‘rare’?’
Package leaflet
How many people are affected by a side effect
if it is ‘rare’? (%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 95.4 1.5 3.1 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 96.0 4.0 0 75
DE-QRD-template-7.3.1-short text 90.3 5.6 4.2 72
DE-QRD-template-8-short text 98.6 1.4 0 73
DE-Model-template-BfArM text 93.5 2.2 4.3 93
DE-QRD-template-7.3.1-BfArM text 90.3 7.5 2.2 93
DE-QRD-template-8-BfArM text 92.6 6.4 1.1 94
EN = English, DE = German, n = number of participants
The SmPC Guideline describes a convention which should be used for frequency groupings e.g. ‘rare
(≥1/10,000 to <1/1,000)’ which is most closely adhered to in QRD template 7.3.1184
. This definition
clearly thereby defines that the frequency of rare side effects is that less than 1 in 1,000 users are affected.
Due to the complexity of this manner of description, the method used in the model template was
developed and tested in a previous study52,60
. However, the formulation used in QRD template 8 most
frequently led to an overestimation of the frequency of side effects when participants were asked how
often a ‘rare’ side effect occurs (table 59). The method of description used in the model template caused
the least overestimation of frequency.
115
Table 59: Answers to the question: ‘How many people are affected by a side effect if it is rare?’
Description of frequency provided by the
participants
Subjects (%)
QRD-
template
7.3.1
QRD-
template 8
Model
template
DE UK DE UK DE UK
1 - 10 people from 10,000 1.9 3.2 0 0 90.2 97.0
Less than 1 in 1000 but more than 1 in 10,000 64.3 82.3 0 1.5 0 0
1 in 1000* 23.0 12.9 97.5 98.5 1.8 0
1 in 10* 0 0 0.6 0 1.2 0
1 in 10,000 6.4 1.6 0.6 0 1.8 1.5
1000 to 10,000 1.3 0 0 0 0 0
1 to 10 in 1000* 0 0 0 0 2.5 0
10 from 10,000* 0 0 0 0 2.5 1.5
1 from 100* 2.5 0 1.2 0 0 0
<0.1 % - >0.01 % 0.6 0 0 0 0 0
Number of participants who provided frequencies in
numbers
157 62 163 65 163 67
(Grey shading shows the method of frequency description used for each template version. * An asterisk
indicates overestimation of the frequency compared to the SmPC definition)
Participants were also asked to identify in which frequency group a side effect belonged if it affected 5 in
100 people. QRD template 8 readers had great problems deriving this information from the leaflet in all
three text versions (table 60). There were significant differences in the number of correct answers
provided between all leaflet versions (p ≤ 0.031, appendices 14, 15 and 16). With regard to the number of
not found answers in the short English text, significant differences were found between the model
template and QRD template 8 (p = 0.013) and QRD templates 7.3.1 and 8 (p = 0.049, appendix 20). For
the German long BfArM text and short text versions, significant differences in the number of not found
answers were also found between the model template and QRD template 8, and QRD template 7.3.1 and 8
(p ≤ 0.001, appendices 21 and 23). The model template in England produced significantly fewer wrong
answers than either of the QRD templates (p ≤ 0.002, appendix 17). In Germany, there was a significant
difference in the number of wrong answers between all template versions regardless of whether long or
short text had been read; however, with an advantage for the model template (p ≤ 0.013, appendices 18
and 19). The most common wrong answer given when leaflets with QRD template 7.3.1 and 8 had been
116
read was that the participants believed that a side effect which affected 5 in 100 people was uncommon
rather than common.
Table 60: Percent correct, wrong and not found answers for each package leaflet for the question
‘In which of the side effect frequency groups does the following frequency: ‘affects 5 in 100 people’
belong?’
Package leaflet
In which of the side effect frequency groups
does the following frequency: ‘affects 5 in 100
people’ belong? (average (%)) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 85.1 3.0 11.9 67
EN-QRD-template-7.3.1-short text 63.1 21.5 15.4 65
EN-QRD-template-8-short text 36.9 33.8 29.2 65
DE-Model-template-short text 85.3 2.7 12.0 75
DE-QRD-template-7.3.1-short text 70.8 22.2 6.9 72
DE-QRD-template-8-short text 34.2 31.5 34.2 73
DE-Model-template-BfArM text 75.3 7.5 17.2 93
DE-QRD-template-7.3.1-BfArM text 60.2 23.7 16.1 93
DE-QRD-template-8-BfArM text 29.8 30.9 39.4 94
EN = English, DE = German, n = number of participants
Knowing how to act is important if any side effects should occur, that is to contact a healthcare
professional. The wording at the end of section 4 regarding how to act when side effects occur differed
between each version of the leaflet as shown:
Model template - ‘Always inform your doctor or pharmacist if you notice side effects’.
QRD template 7.3.1 - ‘If any of the side effects gets serious, or if you notice any side effects not
listed in this leaflet, please tell your doctor or pharmacist’51
.
QRD template 8 - ‘If you get any side effects, talk to your doctor, pharmacist or nurse. This includes
any possible side effects not listed in this leaflet’49
.
The wording in QRD templates 7.3.1 and 8 reflects the mandatory statements included in these versions.
Patients were asked how to act if they should notice the side effect ‘runny nose’. QRD template 8
117
provided the most correct answers for short and long text versions in both countries (table 61). There was
a significant difference between the number of correct answers in the long text version between the model
template and QRD template 8 in Germany (p = 0.009, appendix 16). In England there were significant
differences in the number of correct answers between the model template and QRD template 7.3.1
(p < 0.001), QRD template 7.3.1 and 8 (p < 0.001) and the model template and QRD template 8
(p = 0.012) (appendix 14).
The difference in the number of wrong answers was significant between the model template and QRD
template 7.3.1, but also between QRD template 7.3.1 and QRD template 8 (p < 0.001, appendix 17) in
England. There were also significant differences in the number of not found answers between the model
template and QRD template 8 (p = 0.021, appendix 20) and the QRD template 7.3.1 and QRD template 8
(p < 0.001, appendix 20). In Germany the number of wrong answers found was significant for the short
text between QRD template 7.3.1 and QRD template 8 (p = 0.008, appendix 18). The number of not found
answers was significant in the German long BfArM text version between the model template and both
QRD templates (p ≤ 0.005, appendix 23).
The large number of wrong answers for QRD template 7.3.1 was caused by participants repeating the
template wording that a doctor should be consulted only if the side effect gets serious and not that they
should consult a doctor in the case of any side effects. This wording could be also the reason for the large
number of not found answers in England using QRD template 7.3.1.
Table 61: Percent correct, wrong and not found answers for each package leaflet for the question
‘What should you do if you notice the side effect runny nose?’
Package leaflet
What should you do if you notice the side
effect runny nose? (%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 82.1 3.0 14.9 67
EN-QRD-template-7.3.1-short text 26.2 47.7 26.2 65
EN-QRD-template-8-short text 95.4 1.5 3.1 65
DE-Model-template-short text 78.7 6.7 14.7 75
DE-QRD-template-7.3.1-short text 69.4 15.3 15.3 72
DE-QRD-template-8-short text 83.6 1.4 15.1 73
DE-Model-template-BfArM text 50.5 6.5 43.0 93
118
Package leaflet
What should you do if you notice the side
effect runny nose? (%) n
Correct
answers
Wrong
answers
Not found
answers
DE-QRD-template-7.3.1-BfArM text 55.9 20.4 23.7 93
DE-QRD-template-8-BfArM text 69.1 8.5 22.3 94
EN = English, DE = German, n = number of participants
Some side effects are so serious that a doctor should be consulted immediately and the medication should
be discontinued. In leaflets with QRD template 8, these most serious side effects were listed at the start of
section 4 as recommended. The model template included these side effects in bold type with the advice
that a doctor should be contacted immediately, and leaflets with QRD template 7.3.1 had a section
‘countermeasures’ where symptoms of the very serious side effects and the instruction to contact a doctor
were included.
In Germany, participants who had read both short and long leaflets with QRD template 8 provided the
most correct answers, while readers of package leaflets with QRD template 7.3.1 gave the most correct
answers in England (table 62). However, there were no significant differences found in the number of
correct or wrong answers provided for any template versions. For the number of not found answers, a
significant difference was found for the long BfArM text versions between the model template and both
QRD templates (p ≤ 0.021, appendix 22).
Table 62: Percent correct, wrong and not found answers for each package leaflet for the question
‘Name one side effect which requires that you immediately contact a doctor.’
Package leaflet
Name one side effect which requires that you
immediately contact a doctor. (%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 88.1 9.0 3.0 67
EN-QRD-template-7.3.1-short text 96.9 1.5 1.5 65
EN-QRD-template-8-short text 93.8 4.6 1.5 65
DE-Model-template-short text 80.0 14.7 5.3 75
DE-QRD-template-7.3.1-short text 86.1 9.7 4.2 72
DE-QRD-template-8-short text 93.2 6.8 0 73
119
Package leaflet
Name one side effect which requires that you
immediately contact a doctor. (%) n
Correct
answers
Wrong
answers
Not found
answers
DE-Model-template-BfArM text 78.5 9.7 11.8 93
DE-QRD-template-7.3.1-BfArM text 75.3 22.6 2.2 93
DE-QRD-template-8-BfArM text 84.0 14.9 1.1 94
EN = English, DE = German, n = number of participants
4.7.9 Analysis of comprehensibility and ease of location of information in section 5 of the package
leaflet
For some medicines certain storage conditions are required in order to maintain efficacy. Of vital
importance is that all medicines are stored out of the reach of children, therefore location of this
information contained in section 5 was examined. In England 100 % correct answers were given for
leaflets with the model template and QRD template 8 (table 63). In Germany, participants using the QRD
template 8 gave the greatest number of correct answers with both long and short text versions. But there
were no significant differences found in the number of correct answers, wrong answers or not found
answers for any template versions meaning all three template versions were equally good regarding
locatability and comprehensibility of storage information.
120
Table 63: Percent correct, wrong and not found answers for each package leaflet for the question
‘How should Enal be stored in relation to children?’
Package leaflet
How should Enal be stored in relation to
children? (%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 98.5 0 1.5 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 97.3 1.3 1.3 75
DE-QRD-template-7.3.1-short text 95.8 2.8 1.4 72
DE-QRD-template-8-short text 98.6 0 1.4 73
DE-Model-template-BfArM text 97.8 0 2.2 93
DE-QRD-template-7.3.1-BfArM text 95.7 4.3 0 93
DE-QRD-template-8-BfArM text 98.9 0 1.1 94
EN = English, DE = German, n = number of participants
4.7.10 Analysis of comprehensibility and ease of location of information in section 6 of the package
leaflet
The active ingredient ‘enalapril maleate’ is only listed in section 6 of the model template. For template
version 7.3.1 the active ingredient is listed at the top of the leaflet under the product name and then again
in section 6. Template 8 contains the name of the active ingredient three times; twice as mentioned for
template 7.3.1 and then again in section 1 in the first sentence ‘Enal contains enalapril’. The most common
incorrect answer was due to a misunderstanding that the pharmaceutical group ‘ACE-inhibitor’ was the
active ingredient, a problem which is mainly due to the wording in the BfArM text version where the first
sentence of section 1 reads ‘Enal is an ACE-inhibitor’. In England, 100 % correct answers were given for
both the model template and QRD template 7.3.1, while in Germany, the most correct answers were given
for QRD template 8 for both long and short text versions (table 64). However, there were no significant
differences found in the number of correct, wrong or not found answers for any template versions
indicating that mentioning the active ingredient once in the package leaflet is sufficient.
121
Table 64: Percent correct, wrong and not found answers for each package leaflet for the question
‘Name the active substance in Enal’.
Package leaflet
Name the active substance in Enal.
(%) n
Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 98.5 0 1.5 65
DE-Model-template-short text 92.0 1.3 6.7 75
DE-QRD-template-7.3.1-short text 95.8 1.4 2.8 72
DE-QRD-template-8-short text 98.6 0 1.4 73
DE-Model-template-BfArM text 78.5 14.0 7.5 93
DE-QRD-template-7.3.1-BfArM text 75.3 23.7 1.1 93
DE-QRD-template-8-BfArM text 81.9 12.8 5.3 94
EN = English, DE = German, n = number of participants
A picture of a tablet being broken was included in leaflets with short text versions. In the long BfArM text
leaflets with QRD template 8, the user was told that the tablet could be divided in two equal doses which
is an optional sentence in this template version. Use of the BfArM version of the enalapril text led to
omission of information regarding whether the tablet can be divided in leaflets with QRD template 7.3.1
or model template. In England, 100% correct answers were given for all leaflets. For the short text
versions in Germany, 100% correct answers were given when QRD template 7.3.1 or 8 had been used in
the leaflet. There were no significant differences found in the number of correct, wrong or not found
answers for any short text leaflets between template versions (table 65).
For the long BfArM versions of the leaflet in Germany there was a significant difference in the number of
correct answers provided between the model template and QRD template 8 (p = 0.001) and the QRD
template 7.3.1 and QRD template 8 (p = 0.024, appendix 16). The number of not found answers was also
significant between the model template and QRD template 7.3.1 (p = 0.029) and the model template and
QRD template 8 with the BfArM text (p < 0.001, appendix 22).
122
Table 65: Percent correct, wrong and not found answers for each package leaflet for the question
‘Can this tablet be divided?’
Package leaflet Can this tablet be divided? (%)
n Correct
answers
Wrong
answers
Not found
answers
EN-Model-template-short text 100 0 0 67
EN-QRD-template-7.3.1-short text 100 0 0 65
EN-QRD-template-8-short text 100 0 0 65
DE-Model-template-short text 97.3 1.3 1.3 75
DE-QRD-template-7.3.1-short text 100 0 0 72
DE-QRD-template-8-short text 100 0 0 73
DE-Model-template-BfArM text 37.6 23.7 38.7 93
DE-QRD-template-7.3.1-BfArM text 48.4 28.0 23.7 93
DE-QRD-template-8-BfArM text 66.0 20.2 13.8 94
EN = English, DE = German, n = number of participants
4.8 Participants’ opinions on the package leaflet printed in the three templates
In section 2 of the questionnaire, the opinion of the participants was asked to 15 aspects relating to the
package leaflet. A Likert scale of five categories was used to evaluate the responses and coded in the
SPSS data set with the categories ranging from 1 for ‘yes’, that is total agreement with the statement, to
category 5 for ‘no’, total disagreement (table 2 in ‘Materials and methods’ - section 3.3.4).
4.8.1 Opinions on the structure of the package leaflet
The participants’ opinions on the structure of the package leaflet were mostly positive and very similar for
all leaflets regardless of the length of the text or template used. No significant differences were found
between templates used for the opinions on whether the information requested in the questionnaire’s part 1
was easy to find, or if all the information which was important was at the start of the leaflet.
A significant difference was found in the opinions on whether each subheading clarifies the information
contained in the following section between QRD template 7.3.1 and QRD template 8 when the long
BfArM text had been used (p = 0.010). No further significant differences were found here (table 66).
123
Table 66: Participants opinions on the structure of the package leaflet
Package leaflet
Statement
n The information requested in part
1 was easy to find.
Each subheading clarifies the
information contained in the
following section.
I found all information which is of
importance to me at the beginning of
this package leaflet.
Calculated median Opinion Calculated median Opinion Calculated median Opinion
EN-Model-template-short text 1.82 mostly yes 1.39 yes 2.45 mostly yes 67
EN-QRD-template-7.3.1-short text 1.75 mostly yes 1.44 yes 2.29 mostly yes 65
EN-QRD-template-8-short text 1.75 mostly yes 1.32 yes 2.18 mostly yes 65
DE-Model-template-short text 1.65 mostly yes 1.23 yes 2.10 mostly yes 75
DE-QRD-template-7.3.1-short text 1.72 mostly yes 1.28 yes 2.10 mostly yes 72
DE-QRD-template-8-short text 1.64 mostly yes 1.27 yes 2.29 mostly yes 73
DE-Model-template-BfArM text 2.25 mostly yes 1.43 yes 2.55 neutral 93
DE-QRD-template-7.3.1-BfArM text 2.51 neutral 1.54 mostly yes 2.63 neutral 93
DE-QRD-template-8-BfArM text 2.27 mostly yes 1.36 yes 2.69 neutral 94
EN = English, DE = German, n = number of participants
124
4.8.2 Opinions on the comprehensibility of the package leaflet
Participants were of the opinion that the short text package leaflets were easy to understand and a neutral
assessment was provided in the case of the longer BfArM text when using the QRD templates 7.3.1 or 8.
Significant differences were found in the responses in England between the QRD template 7.3.1 and QRD
template 8 (p = 0.015) and in Germany for the BfArM text between the model template and QRD template
7.3.1 (p = 0.045). No further significant differences were found for opinions on how difficult the package
leaflets were to understand (table 67).
Similar opinions as to whether complicated sentences had been used were found for all leaflet versions and
participants found that the longer BfArM text contained difficult words. No significant differences between
the three template versions of each package leaflet group were found as to whether complicated sentences
or difficult words had been used in the package leaflet (table 67).
125
Table 67: Participants opinions on the comprehensibility of the package leaflet
Package leaflet
Statement
The content of this package leaflet
was easy to understand.
Complicated sentences were not
used in this package leaflet.
This package leaflet does not
contain difficult words. n
Calculated median Opinion Calculated median Opinion Calculated median Opinion
EN-Model-template-short text 1.76 mostly yes 1.80 mostly yes 1.78 mostly yes 67
EN-QRD-template-7.3.1-short text 1.92 mostly yes 1.76 mostly yes 1.77 mostly yes 65
EN-QRD-template-8-short text 1.64 mostly yes 1.65 mostly yes 1.69 mostly yes 65
DE-Model-template-short text 1.57 mostly yes 1.60 mostly yes 2.41 mostly yes 75
DE-QRD-template-7.3.1-short text 1.70 mostly yes 1.70 mostly yes 2.39 mostly yes 72
DE-QRD-template-8-short text 1.61 mostly yes 1.59 mostly yes 2.33 mostly yes 73
DE-Model-template-BfArM text 2.38 mostly yes 2.68 neutral 4.21 mostly no 93
DE-QRD-template-7.3.1-BfArM text 3.00 neutral 2.90 neutral 4.38 mostly no 93
DE-QRD-template-8-BfArM text 2.55 neutral 3.15 neutral 4.30 mostly no 94
EN = English, DE = German, n = number of participants
126
4.8.3 Opinions on the information contained in the package leaflets
Participants in general felt well informed from the information contained in the package leaflet and there
was only a significant difference found between QRD template 7.3.1 and QRD template 8 in England
(p = 0.045). No other significant differences were found between template versions (table 68).
In Germany, there was a significant difference in participants’ responses as to whether the package leaflet
contained too much information between the model template and QRD template 7.3.1 when the BfArM text
had been used (p = 0.031). No other significant differences were found between template versions with
regard to this question or the opinions on whether information on the medicine was missing from the leaflet.
Participants mostly agreed that the package leaflet provided all the instructions needed to use the medicine
regardless of the template or text version which had been used. When the BfArM text had been used there
was a significant difference in the participants’ opinion between the model template and QRD template
7.3.1 (p = 0.004) and the QRD template 7.3.1 and QRD template 8 (p = 0.004), otherwise no significant
differences were found.
127
Table 68: Participants’ opinion on the information contained in the package leaflet
Package leaflet
Statement
I feel well informed from the
information contained within
this package leaflet.
This package leaflet did
not contain too much
information for me.
No information about the
medicine is missing from
the package leaflet.
This package leaflet
provided all the
instructions I needed to
use the medicine. n
Calculated
median Opinion
Calculated
median Opinion
Calculated
median Opinion
Calculated
median Opinion
EN-Model-template-short text 1.49 yes 2.07 mostly yes 2.11 mostly yes 1.49 yes 67
EN-QRD-template-7.3.1-short text 1.59 mostly yes 2.32 mostly yes 2.11 mostly yes 1.57 mostly yes 65
EN-QRD-template-8-short text 1.41 yes 2.54 neutral 1.90 mostly yes 1.38 yes 65
DE-Model-template-short text 1.48 yes 2.21 mostly yes 1.67 mostly yes 1.52 mostly yes 75
DE-QRD-template-7.3.1-short text 1.48 yes 2.33 mostly yes 1.51 mostly yes 1.52 mostly yes 72
DE-QRD-template-8-short text 1.39 yes 2.24 mostly yes 1.50 yes 1.52 mostly yes 73
DE-Model-template-BfArM text 1.74 mostly yes 3.13 neutral 1.73 mostly yes 1.66 mostly yes 93
DE-QRD-template-7.3.1-BfArM text 1.99 mostly yes 3.76 mostly no 1.98 mostly yes 2.16 mostly yes 93
DE-QRD-template-8-BfArM text 1.82 mostly yes 3.63 mostly no 1.86 mostly yes 1.76 mostly yes 94
EN = English, DE = German, n = number of participants
128
4.8.4 Opinions on the readability and motivation to read the package leaflet
Participants who had read a long BfArM version of the package leaflet were less motivated to read the
leaflet further than those who had read short versions of the leaflet (table 69). For the short text version in
Germany there was a significant difference found between participants’ motivation to read the leaflet
between the model template and QRD template 7.3.1 (p = 0.014) and the model template and QRD template
8 (p = 0.004). No other significant differences in motivation were found between templates.
All participants were mostly of the opinion that the text was easy to read and no significant differences were
found between leaflet versions.
Table 69: Participants opinion on the readability and motivation to read the package leaflet
Package leaflet
Statement
n
The first impression of
this package leaflet
motivated me to read
further.
The text is easy to read.
Calculated
median Opinion
Calculated
median Opinion
EN-Model-template-short text 2.93 neutral 1.53 mostly yes 67
EN-QRD-template-7.3.1-short text 2.68 neutral 1.40 yes 65
EN-QRD-template-8-short text 2.49 mostly yes 1.44 yes 65
DE-Model-template-short text 2.29 mostly yes 1.25 yes 75
DE-QRD-template-7.3.1-short text 2.73 neutral 1.31 yes 72
DE-QRD-template-8-short text 2.82 neutral 1.36 yes 73
DE-Model-template-BfArM text 3.73 mostly no 1.94 mostly yes 93
DE-QRD-template-7.3.1-BfArM
text 4.00 mostly no 2.20 mostly yes 93
DE-QRD-template-8-BfArM text 4.11 mostly no 2.16 mostly yes 94
EN = English, DE = German, n = number of participants
129
4.8.5 Opinions on confidence in the package leaflet and the medicine
Whether a patient takes a medicine or not can be affected by concerns which develop after reading the
leaflet. Participants’ response as to whether the content of the package leaflet raised their concerns about
using the medicine were usually neutral, or they had no confidence in taking the medicine (table 70). There
were significant differences found in Germany for the short text between the model template and QRD
template 7.3.1 (p = 0.037) and the BfArM text between the model template and QRD template 8
(p = 0.023). Further significant differences were not found.
Regardless of which text had been used or template, participants mostly agreed that taking the medicine
outweighed the potential risks (table 70). No significant differences were found here between template
versions in any leaflet group.
In Germany, participants were mainly of a neutral opinion in response to the question ‘Would you like all
package leaflets to be similar to this one?’ (table 70). QRD template 8 was evaluated most negatively for the
BfArM text version. There were significant differences found regarding the statement ‘Would you like all
package leaflets to be similar to this one?’ for the long BfArM text version between the model template and
QRD template 7.3.1 (p = 0.041) and the model template and QRD template 8 (p = 0.008). In England, no
significant differences were found between template versions or in Germany between the short text versions
of the package leaflet.
130
Table 70: Participants’ opinions on confidence in the package leaflet and the medicine
Package leaflet
Question
n
The content of this package
leaflet does not raise my
concerns about using this
medicine.
Does the benefit of taking this
medicine outweigh the
potential risks?
Would you like all package
leaflets to be similar to this one?
Calculated
median Opinion
Calculated
median Opinion
Calculated
median Opinion
EN-Model-template-short text 3.64 mostly no 2.32 mostly yes 2.31 mostly yes 67
EN-QRD-template-7.3.1-short text 3.80 mostly no 2.34 mostly yes 2.30 mostly yes 65
EN-QRD-template-8-short text 3.50 neutral 2.23 mostly yes 2.08 mostly yes 65
DE-Model-template-short text 2.89 neutral 2.34 mostly yes 1.93 mostly yes 75
DE-QRD-template-7.3.1-short text 3.34 neutral 2.63 neutral 2.15 mostly yes 72
DE-QRD-template-8-short text 3.21 neutral 2.67 neutral 2.09 mostly yes 73
DE-Model-template-BfArM text 3.31 neutral 2.56 neutral 2.63 neutral 93
DE-QRD-template-7.3.1-BfArM text 3.74 mostly no 2.62 neutral 3.44 neutral 93
DE-QRD-template-8-BfArM text 3.76 mostly no 2.78 neutral 3.54 mostly no 94
EN = English, DE = German, n = number of participants
131
4.9 Participants’ additional opinions on the package leaflet and suggestions for what should be
included or deleted
Layout and design were mentioned in the free-text field at the end of the questionnaire as being a positive
aspect for all package leaflets regardless of the template used (table 71). The package leaflet with the model
template and short text in Germany were the most liked in terms of layout and design with 53 % of the 75
readers who had read this version noting these as positive aspects. The length of the leaflet was considered
best for leaflets with the model template and both the long and short text versions. In England,
comprehensibility was often noted as being a positive feature of all package leaflets. One participant noted
that they liked the contents list in the leaflet with the model template and BfArM text although there was no
contents list present in this version of the package leaflet.
132
Table 71: What the participants liked most about each leaflet noted in the free-text field at the end of the questionnaire
Package leaflet
Number of participants who commended the aspect of the package leaflet mentioned below
No info.
missing
Layout and
design
Readability
of font
Length of
leaflet
Compre-
hensibility
Order
of info.
Side effects
described well
Contents list Other n
EN-Model-template-short text 3 27 7 10 22 3 1 0 (no index) 1 67
EN-QRD-template-7.3.1-short
text 5 29 11 3 24 3 0 0 1 65
EN-QRD-template-8-short text 6 26 7 1 29 4 2 0 1 65
DE-Model-template-short text 5 40 17 11 13 4 1 0 (no index) 5 75
DE-QRD-template-7.3.1-short
text 5 28 11 3 15 12 0 1 10 72
DE-QRD-template-8-short text 6 28 14 3 13 9 0 3 10 73
DE-Model-template-BfArM
text 14 29 11 9 14 13 0 1 (no index) 6 93
DE-QRD-template-7.3.1-
BfArM text 7 23 13 1 10 18 3 1 4 93
DE-QRD-template-8-BfArM
text 17 32 7 0 9 17 3 2 2 94
EN = English, DE = German, n = number of participants who had read the leaflet, N.B. Some participants provided more than one opinion and some gave no
opinion
133
The length of the leaflet was the factor that many participants disliked for the long BfArM text versions
regardless of the template used with around 50 % of readers noting this as a negative aspect for each template
(table 72). The comprehensibility was also perceived as being a negative factor for the long BfArM text
versions. Although only the short text version had been used in England, around 30 % of the readers still
found the length of the leaflet and around 10 % the list of side effects to be too long regardless of the template
used. The list of marketing authorisation holders was mentioned specifically as being disliked by several
readers.
134
Table 72: What the participants disliked about the package leaflet noted in the free-text field at the end of the questionnaire
Package leaflet
Number of participants who criticised aspect of the package leaflet mentioned below
The
inform-
ation
provided
Layout
and
design
Trust in
the
medicine
Read-
ability
of font
Length
of
leaflet
Compre-
hensib-
ility
Order
and
structure
of
inform-
ation
Long list of
side effects
You
should
always
ask the
doctor
MAH
represent
-tatives’
list
Other
n
EN-Model-template-short text 1 1 - 2 20 10 - 10 - 0 (no list) 10 67
EN-QRD-template-7.3.1-short text 0 0 - 0 25 2 - 9 - 1 15 65
EN-QRD-template-8-short text 4 3 - 2 20 2 - 7 - 4 11 65
DE-Model-template-short text 0 2 0 0 4 2 1 8 2 0 (no list) 10 75
DE-QRD-template-7.3.1-short text 1 0 1 3 5 1 0 5 0 0 11 72
DE-QRD-template-8-short text 0 1 0 1 7 1 0 2 2 7 9 73
DE-Model-template-BfArM text 2 1 0 2 43 14 0 2 0 0 (no list) 7 93
DE-QRD-template-7.3.1-BfArM
text 3 9 0 2 45 6 0 1 0 2 4 93
DE-QRD-template-8-BfArM text 1 7 0 4 50 9 0 0 0 2 5 94
EN = English, DE = German, n = number of participants who had read the leaflet, N.B. Some participants provided more than one opinion and some gave no opinion
135
When participants were asked what they thought should be deleted in the package leaflet, the most
frequently crossed out information was the MAH representatives’ list when present (11.1 to 25.5 % of the
participants, table 73). Interestingly, approximately double the amount of readers deleted the list when QRD
template 8 had been used rather than QRD template 7.3.1 regardless of whether the long or short text
version had been read. The picture of the tablet being divided, which was included in the short text versions,
was also deleted by around 5 % of the readers in England.
136
Table 73: What the participants thought should be deleted in each package leaflet noted in the free-text field at the end of the questionnaire
Content deleted
Package leaflet
EN-Model-
template-
short text
EN-QRD-
template-7.3.1-
short text
EN-QRD-
template-8-
short text
DE-Model-
template-
short text
DE-QRD-
template-7.3.1-
short text
DE-QRD-
template-8-
short text
DE-Model-
template-
BfArM text
DE-QRD-
template-7.3.1-
BfArM text
DE-QRD-
template-8-
BfArM text
Information box 0 0 0 0 1 0 0 0 0
Contents list 0 3 2 0 1 2 0 2 0
Picture of tablet
dividing 4 3 5 0 0 1 0 0 0
Section 1 1 0 0 1 0 0 0 0 0
Section 2: Contra-
indications 2 0 1 1 0 0 0 0 1
Section 2:
Warnings and
precautions
3 3 4 1 1 0 0 1 4
Section 2:
Interactions 3 2 3 1 0 0 2 5 5
Section2: Food
and drink 0 1 0 1 0 0 1 0 0
Sections 2: Ability
to drive 0 0 0 1 0 0 0 0 0
137
Content deleted
Package leaflet
EN-Model-
template-
short text
EN-QRD-
template-7.3.1-
short text
EN-QRD-
template-8-
short text
DE-Model-
template-
short text
DE-QRD-
template-7.3.1-
short text
DE-QRD-
template-8-
short text
DE-Model-
template-
BfArM text
DE-QRD-
template-7.3.1-
BfArM text
DE-QRD-
template-8-
BfArM text
Section 2:
Pregnancy and
breast-feeding
0 0 2 0 0 0 0 0 3
Section 3: Dosage 3 2 4 1 0 0 2 0 4
Section 3: Method
of administration 0 1 2 1 0 0 1 0 1
Section 3:
Duration of
administration
0 0 0 0 0 0 1 0 2
Section 3:
Overdose 0 0 3 0 0 0 1 0 2
Section 3:
Stopping taking
Enal
0 0 0 0 0 0 1 0 0
138
Content deleted
Package leaflet
EN-Model-
template-
short text
EN-QRD-
template-7.3.1-
short text
EN-QRD-
template-8-
short text
DE-Model-
template-
short text
DE-QRD-
template-7.3.1-
short text
DE-QRD-
template-8-
short text
DE-Model-
template-
BfArM text
DE-QRD-
template-7.3.1-
BfArM text
DE-QRD-
template-8-
BfArM text
Section 4: Table
used for
description of side
effects frequency
0 (no table) 6 0 (no table) 0 (no table) 1 0 (no table) 0 (no table) 1 0 (no table)
Section 4: All side
effects 2 0 0 1 0 0 0 0 0
Section 4: All side
effects except
very frequent
0 2 4 1 0 0 2 1 2
Section 4: rare
side effects 0 0 0 0 0 0 2 2 1
Section 4: Very
rare side effects 1 0 0 2 0 0 0 3 1
Composition of
the tablet 1 0 1 0 0 0 2 0 2
139
Content deleted
Package leaflet
EN-Model-
template-
short text
EN-QRD-
template-7.3.1-
short text
EN-QRD-
template-8-
short text
DE-Model-
template-
short text
DE-QRD-
template-7.3.1-
short text
DE-QRD-
template-8-
short text
DE-Model-
template-
BfArM text
DE-QRD-
template-7.3.1-
BfArM text
DE-QRD-
template-8-
BfArM text
MAH
representatives’
list
0 (no list) 11 19 0 (no list) 8 18 0 (no list) 12 24
Other sources of
information 0 0 0 0 0 2 0 1 2
How Enal looks
and contents of
the pack
0 2 3 0 2 2 0 2 3
Storage
information 0 0 0 0 0 1 1 0 3
Date of last
revision of
package leaflet
0 1 0 0 0 1 1 2 2
Participants (n) 67 65 65 75 72 73 93 93 94
EN = English, DE = German, n = number of participants who had read the leaflet
140
Most participants did not want any additional information included in the package leaflet (table 74). In
England however 26 % of the readers of the leaflet with QRD template 7.3.1 requested an explanation of
what ‘special care’ means.
141
Table 74: What the participants thought should be included in the package leaflet noted in the free-text field at the end of the questionnaire
Package leaflet
Number of participants who thought the information mentioned below should be included in the package leaflet
Benefits
of
medicine
Price Tablet
appear-
ance
‘Use by’
date
Rx or
OTC
Website/
NHS direct
no.
What does
‘special
care’ mean
Better
dosage
instruc-
tions
Counter
measures
should
stand out
more
Other n
EN-Model-template-short text 2 0 0 0 2 1 0 4 1 8 67
EN-QRD-template-7.3.1-short text 0 0 1 0 0 1 17 3 4 4 65
EN-QRD-template-8-short text 3 0 0 0 0 2 0 2 0 10 65
DE-Model-template-short text 3 0 2 0 6 0 0 0 0 8 75
DE-QRD-template-7.3.1-short text 2 0 2 1 0 0 0 0 0 6 72
DE-QRD-template-8-short text 3 0 1 0 0 0 0 0 0 4 73
DE-Model-template-BfArM text 2 1 1 0 1 0 0 0 0 9 93
DE-QRD-template-7.3.1-BfArM text 2 0 4 0 0 0 0 0 0 9 93
DE-QRD-template-8-BfArM text 1 0 4 0 0 0 0 0 0 5 94
EN = English, DE = German, n = number of participants who had read the leaflet
142
4.10 Dependence of the readability test results on demographic factors
Factors such as age, education level and number of medicines taken a day were investigated relating to their
influence on the ability to locate and understand information in the package leaflet and the length of time
needed to complete the 26 questions relating to the content of the package leaflet. Participants under 20
years of age answered the 26 content questions most rapidly in Germany but also gave the greatest number
of not found answers (table 75). People aged 60 and over needed the longest time to answer the same
amount of content questions in Germany. In England, participants aged over 60 answered the content
questions most rapidly.
There was a significant difference (p < 0.001) found in the time needed to answer the questions relating to
package leaflets content when using the long BfArM text between participants in the age groups ≤ 19 and
20 - ≤ 39, ≤ 19 and 40 - ≤ 59, and 40 - ≤ 59 and ≥ 60 (appendix 24).
There were no significant differences found between the age groups in England regarding the length of time
needed to answer the content questions. Participants in the 20 - ≤ 39 years age group gave the most correct
answers in Germany with the short text version and those aged ≥ 60 with the long BfArM text version.
The age group 40 - ≤ 59 in England provided the most correct answers. There were no significant
differences in the number of correct answers, wrong answers or not found answers between the age groups
for any leaflet group in England.
The majority of participants took no medicine at the time of the readability test (table 74). There were no
significant differences depending of the number of medicines taken per day relating to the number of
correct, wrong or not found answers for any groups of leaflets. There was however a significant difference
in the length of time needed to answer the questions on content and the number of medicines taken per day
for the long BfArM text version (p≤ 0.016, appendix 25) in Germany.
143
Table 75: Number of correct, wrong and not found answers and time needed to provide information
for 26 questions relating to content itemised according to age group and package leaflet group
summarised for the three readability test rounds
Package leaflet
group
Age group
(years)
Calculated Median
n
Correct
answers
(%)
Wrong
answers
(%)
Not found
answers
(%)
Time to answer 26
content questions
(minutes)
EN-short text
20 - ≤ 39 23 89.5 5.0 4.3 15.6
40 - ≤ 59 12 90.2 5.8 2.1 15.3
≥ 60 34 89.8 4.8 3.4 13.4
DE-short text
≤ 19 5 88.9 3.8 6.4 19.3
20 - ≤ 39 21 91.5 5.4 2.7 20.3
40 - ≤ 59 45 91.0 5.2 2.9 20.6
≥ 60 5 90.1 5.8 4.3 32.0
DE-BfArM text
≤ 19 35 67.5 14.5 16.3 17.3
20 - ≤ 39 13 67.9 14.3 16.0 30.0
40 - ≤ 59 41 75.1 12.1 11.8 32.4
≥ 60 7 77.7 14.9 3.6 52.5
EN = English, DE = German, n = number of participants
Participants who had an education level up to 8th class in Germany provided the lowest number of correct
answers (table 75). However, there was no great variability within the other levels of education and no
significant differences were found in the number of correct answers or time needed to answer content
questions according to education level.
144
Table 76: Number of correct, wrong and not found answers and time needed to answer 26 questions
relating to the content of the package leaflet itemised according to the number of medicines used per
day, summarised for the three readability test rounds
Package leaflet
group
Number of
medicines
taken per
day
n
Average
age
(years)
Calculated Median
Correct
answers
(%)
Wrong
answers
(%)
Not found
answers
(%)
Time to answer
26 content
questions
(minutes)
EN-short text
0 27 48 90.2 4.7 3.2 15.7
1 22 49 90.6 5.2 3.3 19.0
2 12 57 88.5 5.3 3.3 20.0
≥ 3 8 61 87.5 5.1 4.4 21.6
DE-short text
0 50 40 90.0 5.4 3.4 20.6
1 17 39 92.9 4.0 2.6 19.7
2 4 42 91.5 3.8 4.9 22.5
≥ 3 5 69 88.8 6.9 4.8 30.0
DE-BfArM text
0 57 31 79.2 10.8 9.8 24.4
1 24 38 77.2 11.0 9.3 26.3
2 8 48 84.6 11.2 2.9 37.5
≥ 3 7 54 78.6 14.8 6.1 40.0
EN = English, DE = German, n = number of participants
145
Table 77: Number of correct, wrong and not found answers and length of time needed to answer 26
questions on content of the package leaflet according to education level
Package leaflet
group
Level of
education n
Calculated Median
Correct
answers (%)
Wrong
answers (%)
Not found
answers (%)
Time to
answer 26
content
questions
(minutes)
EN-short text
10th class 5 92.3 5.5 2.5 19.6
A-levels 7 88.5 4.6 3.3 16.5
Polytechnic
college 5 91.2 4.5 2.6 21.3
University 46 89.7 5.1 3.3 19.2
Other 6 88.5 5.6 5.4 20.0
DE-short text
8th class 7 88.0 6.6 5.0 28.9
10th class 27 90.7 5.5 3.3 19.9
A-levels 9 94.1 2.2 2.3 22.0
Polytechnic
college 4 91.7 5.2 2.7 18.3
University 11 91.5 4.7 3.1 19.7
Other 18 87.7 6.1 4.3 25.7
DE-BfArM text
8th class 42 69.2 15.7 12.8 20.2
10th class 12 79.0 10.2 10.6 21.0
A-levels 10 86.5 7.4 5.0 31.9
Polytechnic
college 8 85.0 9.8 5.1 35.0
University 18 84.2 7.7 7.7 31.4
Other 6 81.5 13.2 3.6 32.5
EN = English, DE = German, n = number of participants
146
5. Discussion
5.1 Qualifying the research context
Although the QRD template has been used since 1996, studies regarding its readability are scarce, a
situation which is contrary to the fact that testing of package leaflets themselves is mandatory before they
are accepted by the authorities, and the fact that the QRD template must be used for each package leaflet
distributed within the European Union and connected countries. The demanded readability testing by the
European Commission of package leaflets has also been shown to be beneficial and improve package
leaflets’ readability185
. Due to publication of QRD template version 8 (for centralised approved medicines)
and version 2 (for other medicines) in 2011, headings and mandatory texts underwent many changes based
on information gained from user testing and feedback from various other sources. The concerned user
testing results are a collection of problems identified from QRD template version 7.3.1, although the
methods and resulting data used to create these amendments remain unpublished49
. The effects of the
increased text volume has not been addressed by the authors of the QRD template even though a study of
a German representative sample of package leaflets in the year 2005 found that an average of 17.7 % of
the volume of text was caused by the QRD template54
. The study by Fuchs et al. published in 2010 also
demonstrated that over a 5 year period, from 2000 to 2004, that the QRD text in the examined 271
package leaflets increased in volume by 25.1 %54
. QRD template wording has been demonstrated in some
cases to cause misunderstanding, which was found during a readability test involving the QRD template 7
in 2006 which identified comprehensibility problems with some of the headings186
. A further readability
test study published in 2012 with 192 participants showed that 14.1 % of incorrect answers from a group
who had read package leaflets with the QRD template were caused by comprehensibility problems with
the template wording52
. In view of the lack of published studies regarding readability of the QRD
template, one focus of this project was to test the QRD template 8 which had just been published at the
start of this study, and is very similar to the current version 9, in comparison to the predecessor template
version, and a model template to identify whether readability and comprehensibility had improved.
Implementation of the QRD template within the European Union, Iceland, Norway and Lichtenstein has
served the purpose of creating uniformity in the structure and content of package leaflets which is
beneficial for patients as the information which they receive with each medicine is therefore organised in
the same way. This is in contrast to some other countries such as the United States where three different
types of patient information exist, each with a differing layout and content187
. Use of a template is not
simply a European Union phenomenon; non-EU countries such as Australia, New Zealand, Switzerland
and the United States also use documents similar to the QRD template for both the package leaflet and
specialist information. A comparative evaluation for consumer medication information was carried out for
the United States, Europe (represented by package leaflets from the United Kingdom) and Australia188
.
147
This study by Raynor et al. published in 2007 involved reviewers evaluating the chosen leaflets and giving
each a score according to whether selected criteria had been adhered to, for example, whether certain
clinical content is present and whether the form it is written in is legible. Wide variation was found in the
quality of the leaflets in terms of content and readability, although it must be taken into consideration that
this rating was largely due to personal opinions of the reviewers involved. The Australian leaflets studied
by Raynor et al. were generally superior followed by those from the United Kingdom (representing
European Union leaflets) and the United States which was suggested to reflect the regulatory context188
.
The lack of clear headings and bullets to enhance readability were mentioned as negative aspects of the
United States leaflets. Certain aspects of package leaflets from the United Kingdom, the United States and
Australia were evaluated positively, for example, the use of phonetic spelling of the name of the medicine
in the United States188
. Phonetic spelling is also suggested in the core CMI from Australia, but is not a
component of the QRD template. The comparative study published by Raynor et al. proposed that leaflets
from Australia and the United Kingdom achieved higher scores than those from the United States as they
included most or all of the relevant information available to health professionals188
. There is relatively
little research and no existing published studies on the content or design of templates used for the package
leaflet, therefore investigation into legislation and guidelines influencing the content of templates from
other countries was considered a further important aspect of the study described in this dissertation.
5.2 Methodology
5.2.1 Analysis of QRD template development up to the present day
Since initial publication of the QRD template in 1996, wide ranging changes in structure, headings,
subheadings and standard text have taken place. No published study was found regarding template
development and therefore part of this work was to analyse versions of the template from the initial
publication to the present day. As only the newest version of the QRD template is available on the EMA
website, it was necessary to request older versions of the QRD template directly from the EMA. After all
versions of the QRD template from the first edition to version 7.3.1 had been kindly provided, the QRD
template for centralised procedures for OTC products was used for further analysis, rather than that for
MRP/DCP procedures, as a consecutive sequence of older versions of this document were available up to
the present day. Only minor differences exist between the template for OTC medicines compared to that
for prescription only medicines, for example, in the phrases provided in the information box at the start of
the template. The template for MRP/DCP procedures differs to that for centralised procedures at the end
of section 6 where instead of a list of representatives of the marketing authorisation holders, the name of
the medicine is provided and the country where it is on sale under the given name. The results thereby
found in this study concerning the template for OTC medicines authorised via a centralised procedure can
148
be extrapolated for the most part to the template for prescription only medicines and that for MRP/DCP
authorisation procedures.
An important component of QRD template analysis was to determine the minimum and maximum number
of words contained in each template version to illustrate how the text volume of the template has
developed over time. The number of words present in the QRD template text framework has previously
been shown to be increasing in volume54,189
, a fact which could lead to longer package leaflets which has
been demonstrated to have a negative effect on locatability of information, reduces motivation to read the
package leaflet and increases the time needed to find specific facts55
. Due to the bracketing convention in
the QRD template, sections of the template can be omitted in the package leaflet which are not relevant to
the described medication. Therefore this bracketing convention was applied to investigate the minimum
number of words which must be used from the template. The choice of parameters which were
investigated in each version of the QRD template were selected to assess whether suggestions from the
Readability Guideline were put into practice by the QRD group. Long sentences of over 20 words should
not be used according to the Readability Guideline from 199836
, and abbreviations should be avoided38
,
therefore these aspects were considered important to analyse. As repeating information causes an increase
in text volume, repeated sentences present in each version of the template were counted. A text
comparison of the main headings, subheadings and standard sentences in each version of the QRD
template was carried out to illustrate how these phrases had developed over time.
5.2.2 The use of templates for the package leaflet in EU and non-EU countries
To meet the aim of comparing the structure and content of information contained in other templates in
comparison to the European Union’s QRD template, countries were chosen as defined by the criteria
described in section 3.2. Although a comparison of templates for the package leaflet was the focus of the
study, the investigation into the history of development of legal directives and guidelines influencing the
content of the package leaflet in the chosen countries was considered a valuable starting point in order to
understand the content of the investigated templates.
A good working knowledge of both the English and German language was an advantage when analysing
the templates from the chosen countries. Conversely, a limitation of this study is therefore that templates
most probably exist in languages other than the two involved which were not included in the investigation.
Other existing templates could be in a different form and potentially better than those investigated. The
collection of countries chosen was also not exhaustive of those where English and German is the main
language spoken, however, the choice included nations from widely separated points on the globe who
published a template via the internet. The necessary directives, guidelines and templates from the selected
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countries were also easily accessible on the internet, and it was possible to contact representatives at the
relevant authorities and be provided with information.
5.2.3 Evaluation of QRD template implementation in package leaflets of centralised approved
medicines
During a time period of two years, all package leaflets for medicines authorised by a centralised approval
procedure and accessible on the EMA website were analysed. A similar download and analysis of QRD
template use in package leaflets of medicines for centralised approved medicines is not known. The
download process of these documents took place three times with a year time gap between each download.
A time gap of one year was considered acceptable between downloads to see how rapidly implementation
of QRD template 8 and subsequently 9 took place. This study highlighted the enormous effort the
pharmaceutical companies and authorities expend in order to ensure up-to-date documents. Over 70 % of
the examined package leaflets were updated between each download, although the updates did not always
affect QRD template use but rather other aspects of the content. This method was chosen as these
documents were publically available and enabled a large number of package leaflets for a wide variety of
medicines to be investigated. Although 616 package leaflets were available at the time of the first
download, it was not possible to analyse all of them due to technical problems. However, only 8.3 % of
the package leaflets could not be analysed, and calculation of the 95 % confidence interval showed that the
remaining sample size of 565 package leaflets is representative of the actual situation of package leaflets
of centralised approved medicines. However, as only package leaflets for centralised procedures were
analysed, differences to the template implementation in package leaflets authorised via purely national
procedures can naturally not be excluded due to the fact that each member state has its own specific
requirements for national legislation. For example, the Danish authorities request additional information
beyond the scope of the QRD template in section 2, 3 and 4 of the package leaflet179
. In section 2 of the
Danish package leaflet the following statement must be present; ‘Please notice that your doctor may have
prescribed the medicinal product for a different therapeutic indication and/or at a different dosage than
stated in the package leaflet. Always follow the doctor’s prescription and the instructions on the dosage
label’179
. However, as the QRD template should also be used for national procedures, existing national
requirements are placed more in the background. Differences in QRD template use for products authorised
via a MR/DC procedure must also be considered, however, are minimal. The QRD template for MR/DC
procedures version 3 only differs to that for centralised approved procedures in the less important
information in section 6 of the package leaflet, where it includes a section for the names of the medicinal
product and member states of the EEA where it is authorised, and does not include the optional list of 30
MAHs representatives. Therefore, the only differences which are to be expected in the implementation of
the QRD template for centrally authorised medicinal products compared to those authorised via a MR/DC
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procedure affect section 6 and not other elements of the template. One point which is however also no
known is how quickly the package leaflets are altered or updated for MR/DC or national procedures
compared to those for centralised approved procedures.
5.2.4 Study design of the readability test involving QRD template version 8, its predecessor and a
model template version
To comply with Articles 59 (3) and 61 (1) of Council Directive 2001/83/EC as amended by Directive
2004/27/EC, Marketing Authorisation Holders must provide evidence that the package leaflet ‘reflects the
results of consultations with target patient groups to ensure that it is legible, clear and easy to use’ and
these results should be presented to the competent authority39,24
. This ruling is intended to ensure that
patients can locate and comprehend key messages in the patient information for a safe and effective use of
medicines. One method of complying with this legal requirement is to carry out a ‘user testing’, the
current gold standard in the EU, of the package leaflet whereby readability of an example is tested with a
group of subjects38,190
. The most frequently used method by MAHs to abide by Article 59 (3) is the
‘Australian’ method of user testing where verbal face-to-face interviews with participants are carried out
in a minimum of two rounds61
. An alternative to this approach is the ‘self-completion’ method which takes
the form of the written readability test. The written readability test method was chosen in this study to
investigate the readability of the QRD templates 7.3.1 and 8, and a model template. This self-completion
way of testing is a strength of the study and offers advantages over the ‘Australian’ method as a more real
life situation is simulated whereby participants receive a package leaflet and questionnaire which they fill
in independently. This method has been validated in a previous study by Fuchs et al. published in 2007
and complies with the guidelines in the European Union53,61
. When this method is used, less external
influence, such as mimics and gestures, is provided by the interviewer themselves compared to when the
interviewer poses the question and fills in the questionnaire, which is essential to compare different leaflet
texts61
. Participants with hearing difficulties could also have problems understanding the interviewer, or
conversely the interviewer may not understand the answer provided and write down an alternative
response. The written readability test also provides the advantage that it was possible to provide the same
conditions in each round of the readability test and country whereby participants received their
instructions via the questionnaire and not from an outside person. A slight deviation to the method
developed by Fuchs et al.53
was used in the readability test in this study as the majority of participants
were allowed to take the package leaflet and questionnaire home to complete, rather than filling it in under
a controlled environment. However, the school classes involved in this study read the material and filled in
the questionnaire under observation by a teacher in the classroom. Theoretically participants who filled in
the questionnaire at home could have gained help from a further person or deliberately written down the
wrong answers, although this behaviour is not to be expected from volunteers. Another point mentioned
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by the CMDh is that in comparison to the Australian method, in the written readability test ‘participants do
have to be capable independently of reading and answering the questionnaire, using only the written
instructions provided’61
. However, it is this fact which ensures identical study conditions in each test
round of this template study. It was also additionally explained to each participant personally how to carry
out the readability test using the provided materials.
As participants in the user test should be representative of everyone who might take the medicine, people
with lower literacy and writing skills must not be excluded. During recruiting in this study, all levels of
education where therefore included and the resulting group of participants provided people with a wide
range of educational background, age and social status. A limitation however of this study could be that all
participants, except for one in England, were native speakers of the language in which the readability test
was carried out, meaning that understanding of the materials provided for the readability test by non-
native speakers, who may not possess such advanced language skills, could not be investigated.
Theoretically, restricted understanding of either German or English could therefore have affected the
results of this study. All participants were also volunteers which may have also caused a bias in the results
due to those involved being interested and willing to read the information and answer the questionnaire. It
is not known how people with no interest in taking part in the study would have performed, although there
is no reason to believe the answers provided would differ.
The study design of the readability test described in this work followed a similar structure to that
recommended by the CMDh61
whereby key messages were identified to test the template text, a
questionnaire was prepared based on these key messages and on overall perception of the document,
followed by completion of the questionnaires by test participants. To test the leaflet using an interview
technique, the Readability Guidelines and the CMDh recommend two test rounds with a minimum of 10
participants in each36,38,61
. The recommended minimum number of 20 participants was exceeded in this
study to a three to four times higher number of people who tested each package leaflet in order to obtain
robust data. A cross-over study design was chosen whereby each participant tested each template as this
allows better comparison of the three templates investigated. A minimum six month time period before
each participant tested a new template version of the leaflet was chosen according to the recommendation
of the MHRA, whereby 6 months is considered sufficient to avoid participants getting used to knowing
where to find information191
. Leaflets prepared with the three templates had an identical font size and type,
paper and print quality. Care was taken that the content of the text provided and layout of information of
both the package leaflets and questionnaire used in both countries was identical to ensure best comparison
of the tested templates.
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5.2.5 Development of package leaflets and questionnaires for the written readability test
Package leaflets were created for the active ingredient enalapril using QRD template 7.3.1, QRD template
8 and a model template which had been tested in previous studies52,53
. The active ingredient enalapril was
chosen as this is a widely used medicine for which a sample text was freely available from the German
authorities BfArM at the start of this study59
. It thereby provided an authentic text which was currently
used at the time for enalapril containing products on the German market independent of the marketing
authorisation holder or manufacturer. In addition, the text for enalapril has been used in a previous study55
and although enalapril is not authorised via a centralised procedure, the type of marketing authorisation for
this active ingredient was irrelevant to this study as the template text was being tested and not information
relating to the product itself.
For the printed material used in this study, a larger type face was used for headings of the main sections
and a smaller font size for the running text. In leaflets printed with QRD template 7.3.1, capitals were used
for the section headings as this was the chosen format in this template version. Bold type was used in
leaflets with the model template to emphasise serious side effects and for all section headings in every
leaflet which is mentioned in the Readability Guideline38
.
The purpose of the readability test in this study was to analyse whether the headings and standard
statements used in two versions of the QRD template or an alternative model template influence patient
understanding in terms of locatability and comprehensibility of information. The questions chosen where
therefore specifically designed to test the text from the template rather than any medicine specific
information. The order in which the questions were presented was randomised as recommended by the
Readability Guideline36
; questions which referred to information in adjacent sections/paragraphs were not
asked in sequence. The study described in this work involved 26 questions relating to content contained in
each package leaflet, 12 -15 questions is considered sufficient to test a leaflet38,178,192
. More than the usual
number of questions was included in order to test double the amount of template text than could otherwise
be carried out. In a previous study, 25 questions relating to content of a package leaflet were used, and the
time expenditure ranged from 5 to 75 minutes (calculated median 20 minutes)52
. This indicated that using
a questionnaire with 26 questions would not overtax participants and that the required time was feasible.
5.3 Comparison of the European Union QRD template to templates used in non-EU countries
The concept of developing a template for the package leaflet in the investigated countries/areas was first
seen in Germany in 1993 followed by the publication of the European QRD template in 1996. Core CMIs
were introduced in New Zealand in 1998 and in Australia in 2001. Although the templates have arisen
from different national legal situations, the order and content of information is surprisingly similar (table
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19). This sequence structure in the QRD template, which arose as a result of implementation of Directive
2004/27/EC24
, has been shown in two previous studies to meet both the needs of specialists and patients
significantly more than previous valid versions12
.
In a similar manner to the annotated versions of the QRD template, the core CMI in Australia provides
precise detail on what to include in each section, while that from New Zealand is very sparse which could
lead to greatly differing information being provided by MAHs in each section. An advantage of the
examined templates from Switzerland, Australia, New Zealand and the current QRD template from the
European Union is that they all provide clear headings placed on a separate line to the main text and
avoided the use of italics and capital letters; both which are advised against in the Readability Guideline
from 200938
. As seen during the analysis of the QRD template development, it is only the most recent
versions of the template which avoid use of both italics and capital letters. However, in the readability test
described in this study, the use of capital letters in package leaflets with QRD template 7.3.1 was never
criticised by the participants.
A study of written medicine information from English speaking countries found that 100 % of Australian
leaflets used in the practice, as well as the majority of leaflets from the United Kingdom, separated
headings from main text193
. Emphasis of section titles in capitalised text has been suggested as being
difficult to read193
. A study involving 224 readers, who analysed various headline styles, concluded that
those in capital letters were significantly less legible than those in lower case194
. Use of capital letters also
takes up a least one-third more space than lower case and reduces speed of reading195
. While QRD
template versions up to 7.3.1 used bold text in capitals for the main section headings, this was changed
from QRD template 8 to lower case letters which can be welcomed as an improvement as bold, lower case
letters have been found to be good for emphasis196,197
.
Legislation, templates and guidelines determine the creation of the package leaflet in the European Union
and Australia. In the European Union the QRD template should be used in conjunction with the
Readability Guideline38
while the writer of the CMI in Australia is told to refer to the Usability
Guidelines146
. Both these guidelines are intended to improve the readability of patient information. In the
United States of America no reference to such documents is present and a study of MedGuides from 2006
to 2011 showed that during this 5 year period that little improvement had been made in readability198
.
Therefore, simply the use of a template to determine structure and content of the patient information
appears not enough to increase readability, but that supplementary guidelines regarding layout, design and
linguistic style could be helpful. The Plain Writing Act was introduced in the United States in 2010 and a
further agency is developing a set of standards for designing materials such as MedGuides which are
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hoped to improve readability198
. A further study published by Luk et al. in 2010 which indicated that use
of templates in combination with usability guidelines is beneficial was carried out whereby 157 samples of
written medicine information were evaluated by three researchers193
. The readability of the leaflets was
assessed using the Flesch-Kincaid Grade Level which is a mathematical formula designed to calculate the
number of years of education generally required to understand a text. This method of assessing readability
greatly differs from the readability tests used in the European Union and Australia whereby real people
test the package leaflets with regard to locatability and comprehension of contents. The latter offers the
advantage that usability is tested in the practice and not calculated using a formula. The results of the
readability test in this study also showed that the number of years of education did not affect how
participants understood the tested package leaflets which indicates that maybe calculating the number of
years of education generally required to understand a text is not the deciding point as to whether the
document is comprehensible to certain users or not. The PAINT1 study with 1105 participants confirmed
this finding53
.
With regard to the ease of readability, Luk et al. found that written medicine information from New
Zealand and Australia was superior to information from the other English speaking countries Canada,
Ireland, United States and the United Kingdom, although all used a conversational tone and active
voice193
. This was attributed by the authors to the fact that the information in Australia and New Zealand
uses a standardised format (dictated by the templates) and compliance with usability guidelines193
. Leaflets
from the Unites States fared worse than the European leaflets examined which was again ascribed to the
lack of standardised guidelines.
It was also of interest to see how different information is included in the package leaflet for the patient in
the examined countries. Statements regarding whether the product is addictive are present in the patient
information from the United States, Australia and New Zealand, self-help methods to improve the medical
condition are found in Australia, New Zealand and Switzerland. Describing the benefits of the medication
to improve patient compliance was seen in all examined templates except that from Switzerland.
Describing the benefits of a certain medicine has been shown to be positive199
and therefore inclusion of
such information in a template might be advantageous.
In Switzerland, the manufacturer of the product does not have to be mentioned in the package leaflet, only
the name and address of the MAH who bring the product onto the market. One study in Germany
involving 855 participants revealed that the name of the MAH and manufacturer are considered the least
important information in the package leaflet23
. In this study, all leaflets contained the name of the
marketing authorisation holder and manufacturer. However, these components were never mentioned
155
when participants were asked what they thought should be deleted in the package leaflet. Nonetheless, as
the name of the MAH is also a component of the outer packaging, its omission from the QRD template for
the package leaflet could be considered. Alternatively, the number of provided addresses could be reduced
to one, such as only the MAH thereby omitting the manufacturer.
5.4 Comparison of comprehensibility, location of information and satisfaction with each
package leaflet tested in the readability test
The increasing volume of text in the QRD template has contributed to the fact that package leaflets are
increasing in length, a fact which is not welcomed by users1. A more compact leaflet in the future has also
been favoured by specialists12
. The study described in this work has shown that it is possible to reduce the
text volume of a package leaflet by use of a model template and consolidating the text information under a
series of bullet points. Using bullet points rather than continuous text to organise lists is considered to
improve readability196
. More concise information in package leaflets with the shorter model template
generally reduced the time needed to find requested information (table 37) and increased the number of
correct answers (table 38). Using QRD template 7.3.1 showed an increase in the number of answers ‘not
found’ or’ incorrect’ in comparison to the model template or QRD template 8 for both long and short text
versions in Germany and in England. This is confirmed in a previous study to mainly be due to difficulties
in comprehension caused by QRD template 7.3.1 wording52
. The fact that more correct answers were
achieved using QRD template 8 compared to QRD template 7.3.1 indicate that the reworded headings and
standard statements have provided better comprehensibility of information. When the long BfArM text
version had been read, participants were significantly more of the opinion that ‘each subheading clarifies
the information contained in the following section’ when QRD template 8 had been used rather than QRD
template 7.3.1 (table 66). For the short text versions in England, participants also felt significantly better
informed from QRD template 8 than QRD template 7.3.1. QRD template 8 therefore does appear to increase
comprehensibility of information in comparison to its predecessor.
Two previous studies with the shorter model template, one involving 1105 participants investigating ten
package leaflets and another with 192 participants testing six leaflets, confirm its’ benefits over the QRD
template as found here52,53
. The study involving 192 participants found on average 18.1 % less time is
needed to locate requested information and 15.7 % more information is found or understood when using the
model template compared to the QRD template, mainly due to template length and difficulties in
comprehensibility52
. Although the described studies tested QRD templates in German which were current at
the time of the research (i.e. year 2000 and 2008), this study provides similar results when comparing the
model template to QRD template 7.3.1 and the current QRD template text (excluding the two
pharmacovigilance implementations in version 9). The study described in this work is also the first to
156
demonstrate that the shorter model template has advantages in the English language. In addition, it also
showed benefits when using a long package leaflet text as found with the long BfArM sample text (section
4.7).
Increasing the amount of text has previously been shown to decrease ability to locate information thereby
discouraging reading of the contents55
. German participants in the study described in this work favoured
leaflets with the model template regardless of whether a long or short text version had been used in terms of
motivation to read the leaflet (table 69). This was significant for the short text version in Germany where
participants were significantly more motivated to read a leaflet with the model template than with either
version of the QRD template demonstrating an advantage of the model template. The length of all three
leaflets with the model template was a fact which was commended in the free text section at the end of the
questionnaire (table 71). Participants were also satisfied with the scope of information which had been
provided as only few mentioned any further aspects which should be included in the package leaflet (table
74). The study of personal opinions of the participants regarding each template revealed that QRD template
8 was always rated better than QRD template 7.3.1 and never worse. However, a further study involving
more participants would provide an additional evaluation of opinions on each template version for the
package leaflet.
Medical terms should be presented in an understandable way for patients with the lay term and a
description first followed by the medical term38
. The Readability Guideline also suggests using a list with
bullet points instead of long paragraphs which can confuse readers38
. The shortened text versions used in
this readability test condensed the information from the BfArM text into a series of bullet points. Although
in all leaflets, medical terms had been explained, participants found the content of leaflets with QRD
template 7.3.1 the most difficult to understand regardless of whether lists with bullet points or full
sentences had been used indicating that the template version influenced readability (table 67).
The order of information contained in the package leaflet and hence listed in the QRD template is
stipulated by the Directive 2004/27/EC24
. The first three sections of the package leaflet thereby contain, in
the following order, information on therapeutic group and indication, followed by contraindications and
precautions, and then dosage and application errors in section 3. This order of information seems to be
acceptable as respondents mostly agreed that all the information which they considered important was
contained at the start of the leaflet (table 66). Previous studies have also confirmed that the specified
sequence structure meets the needs of both patients and specialists12
. The section order was suggested due
to results of earlier research by German scientists200
and implicated within the EU with implementation of
Directive 2004/27/EC24
.
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5.5 Analysis of content, comprehensibility and locatability of information in the QRD template
5.5.1 Comprehension and location of information at the start of the QRD template for the
package leaflet
The information box at the start of the QRD template became a feature of the template text in 1998 with
the 3rd
published edition of the template. It was also a component of the template from the Readability
Guideline published in 199836
. In the information box the instruction was included not to pass the
medicine on to others with similar symptoms as it may harm them. Leaflets with QRD template 7.3.1 and
8 both contained a comparable statement in the information box at the start of the leaflet while the model
template investigated had a similar statement in section 5. No clear advantage was seen for either method
of presenting the information regarding comprehensibility that it should not be given to others. This
indicates that the location of this statement is irrelevant regarding locatability. However, it should also be
taken into account that giving medicines to other people is something that generally should not be done
which could have affected the number of correct answers.
That the medicine is available on prescription was presented in the information box of leaflets with QRD
templates 7.3.1 and 8 and in section 5 of the model template. No significant advantages were seen with
regard to the number of correct answers for providing this information in the information box. However,
the participants who had read a short text leaflet in Germany with the model template provided
significantly more not found answers indicating that location at the start of the leaflet was maybe
important in order to ensure that readers can find this information. However, when taking into
consideration that prescription status is usually a component of the labelling of the package as described in
the ‘Blue-box’ requirements by the CMDh179
, it could be eliminated in the package leaflet.
The general information usually contained in a box at the start of the QRD template and the Swiss
template is not a component of the templates from Australia, New Zealand or the United States.
Additionally, this general information contained at the start of the template is not reflected in any
European Union or national directives and could therefore be removed from the QRD template, especially
as most of the points are repeated elsewhere in the template. The description of what the leaflet is for and
why it has been supplied has also been suggested to be superfluous as package leaflets have been provided
for a long time within the EU and it can reasonably be assumed that patients know why they are contained
in a similar fashion to instructions provided with other products52
. The sentences contained in the
information box of the QRD template 8/9 are enclosed in pointy brackets meaning according to the
bracketing convention that they can be completely excluded.
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In addition, the information box contains many words which are enclosed in further pointy brackets. For
example, for prescription only medicines, strictly applying the optional bracket convention to these further
pointy brackets means compressing the applicable 98 words in the information box by up to 40 %189
if it is
not completely excluded. The only point which was deleted at all by MAHs in the study of package
leaflets of centralised approved medicines was that the medicine should not be passed on to others when
the medicine is only administered by a healthcare professional (table 22). Omission of text phrases in this
introductory box should be recommended to the QRD group and marketing authorisation holders in
general, and especially in the case that this information is listed elsewhere in the package leaflet. The
results from the readability test study described in this work showed that the model template without an
information box was not inferior to either QRD template 7.3.1 or 8. A model template without the
information box has also been found when used in two further studies not to be inferior to those containing
it52,53
. These results in conjunction with the fact that the information box is not a component of the
template in other countries further suggest that this component of the QRD template could be eliminated.
The contents list following the information box in the QRD template also became part of the template text
with publication of version 3 in 1998. The annotated QRD templates 8 and 9 state that user testing has
indicated that most patients value a contents list50,56
, although this data remains unpublished. The contents
list itself is also only of limited use as most package leaflets are not printed as a booklet with page
numbers, but rather on a sheet of paper, and the headings provided only state the order of the included
main sections but not page numbers as to where to find a particular section. Also, for example, the
important subsections contained in section 2 are not listed in the contents list meaning that the reader can
not immediately recognise where to locate certain information such as for interactions with other
medicines.
The analysis of package leaflets of medicines authorised by a centralised procedure showed that 99 % of
the examined leaflets actually contained such as list (table 22). A list of contents is however not a
component of all templates which were examined in the study. The Swiss template and United States
MedGuides appear to function acceptably without one, and in Australia and New Zealand a list of contents
is only required if the leaflet is longer than 4 pages. Use of a model template in two German studies
without a contents list also showed no disadvantages in comparison to those containing one52,53
. The
model template used in this study also demonstrated according to the results provided in chapter 4.7 that a
clear layout and well emphasised headings are sufficient for navigation. The presence of a contents list to
navigate through a booklet appears more meaningful than when used for location of information printed
on a single sheet of paper. Eliminating the index in the QRD template or placing it in optional pointy
brackets is a suggestion for future versions of the QRD template.
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5.5.2 Comprehension and location of information in section 1 of the QRD template for the
package leaflet
QRD template 8 and its update - version 9 - suggest the subdivision of section 1 into three paragraphs:
invented name, active substances and pharamacotherapeutic group followed by therapeutic indications and
then facts on benefits of using the medicine for example under a separate subheading ‘How X works’50
.
The use of subheadings in section 1, as recommended in both annotated QRD template versions, is most
likely beneficial as providing the pharmacotherapeutic group before the indication has been shown to
cause comprehensibility problems12,53
. This order of information however results from Directive
2001/83/EC39
and cannot be changed without amendment of this directive.
Additionally naming the active ingredients in section 1 causes a multiple repeat of this information which
is presented at the start of the package leaflet and then again in section 6 thereby causing unnecessary
increase in the volume of text. Including the active substance name under the name of the medicine at the
beginning of the package leaflet is a requirement of Directive 2001/83/EC, Article 59 (1) (a)(i)39
, but ‘only
where the product contains one active substance and if its name is an invented name’. This means in many
cases that this information is superfluous - a fact which perhaps MAHs and authorities are not aware;
therefore, this is not considered in the current QRD template.
The question also arises as to whether patients or users actually interpret this information at the start of the
package leaflet, because the name(s) of the active substances presented according to the QRD template, is
completely without further context. If the active substances must be included under the medicine name, it
would be better to state ‘Active substances:’ or ‘Active substance’ (in the case of only one) followed by
the names. Furthermore, it has been shown that patients find it sufficient when the names of the active
ingredients are simply included before the list of other ingredients60
. The model template used in this study
only contained the name of the active substance in the list of ingredients in section 6, which did not affect
significantly the readability test results compared to both QRD template versions independent of which
country the package leaflets were readability tested in (table 64).
Only including the active ingredient in section 6 of a model template has also been shown in a previous
study to not cause a significant difference between groups with the model template or QRD template 7.3.1
in the percentage of subjects who could correctly name the active substance52
. Repeating this information
therefore appears unnecessary and simply including the active ingredient with the other components at the
end of the leaflet is satisfactory. However, even though information on ingredients is considered to not be
160
the most important, some patients request that this should be included at the start of the leaflet; however,
the majority preferred it at the end12
.
The most incorrect answers relating to the active substance name in the readability test study were due to
understanding that the pharmaceutical group ‘ACE-inhibitor’ was the active ingredient, a problem which
is due mainly to the wording in the long BfArM sample text version where the first sentence of section 1
reads ‘Enal is an ACE-inhibitor’. Inclusion of the sentence ‘Enal contains enalapril’ in QRD template 8
reduced this problem although the fact that no significant differences were found between template
versions in the number of correct answers provided indicates that this sentence in the QRD template 8 is
redundant and could be deleted. It should also be discussed in the future, whether mentioning the
pharmacotherapeutic group (in this study the term ‘ACE-inhibitor’) is necessary for the patient, as this is
the cause of the problem that the active ingredient is confused with the pharmaceutical group.
Therapeutic indications have been shown to be considered as ‘very important’ by patients12,200
who also
think that this information should be placed at the beginning of the package leaflet12
. All participants who
had read a leaflet with short text and the model leaflet in both investigated countries could state what the
medicine is used to treat (table 41). Wrong answers for leaflets with QRD template 7.3.1 were caused by
participants confusing again the pharmaceutical group ‘ACE-inhibitor’ with the indication, which has also
been found in a previous study52
. This is a problem which resulted from European Directive 2001/83/EC39
and QRD template 7.3.1 where it was necessary to state this information before the indication. Changing
the order of the information in the template could alleviate this problem, although this requires amendment
of the European Union ruling.
Addition of a benefit message in section 1 of the leaflet could aid in subjective benefit/risk perception and
including positive information in the package leaflet about the potential benefits of taking the medicine
may counteract the lists of ‘frightening’ side effects and other warnings which may dissuade a patient
from taking a medicine101
. An exploratory study showed that insertion of a benefit message had a positive
impact on benefit/risk perception as more than 60 % of the people who had read a leaflet with a benefit
message perceived greater benefit for the medicine199
. A further study using textual and numerical benefit
information showed that although participants felt that textual benefit information offered an incentive to
take the medicine, the numerical benefit information provoked feelings of disbelief and shock as the
subjects were surprised that so few people would benefit201
. Including benefits of the medicine was noted
by some participants as information which should additionally be included in the package leaflet.
Although the sentence ‘Studies show that the benefits of Enal prevail with the correct use’ was included at
the start of section 4 of the model template and a benefit statement was included in leaflets with QRD
161
template 8, participants did not have significantly increased belief in the medicines benefits after reading
either of these versions in comparison to QRD template 7.3.1 (table 70). Inclusion of a statement about the
positive benefit of taking a medication has also been shown to have relatively little effect on judgments,
whereas informing people on how to reduce the chances of experiencing side effects was beneficial202
.
5.5.3 Comprehension and location of information in section 2 of the QRD template for the
package leaflet
A major change from QRD template 7.3.1 to 8 was altering the heading ‘Take special care with X’ to
‘Warnings and precautions’ in QRD template 8 followed by the instruction to talk to a healthcare professional
before taking the product49,51
. The former heading failed to provide any additional precautionary information
or actions to take. Participants in this readability test study in England who had received a leaflet with QRD
template 7.3.1 often noted that a description of what ‘special care’ means should be included in the package
leaflet (table 74). A report by Andriesen on experience from previous readability tests involving QRD
template 7.3.1 described that it had been found that the question as to what ‘special care’ means often arises
with this template version186
. In this investigation, two questions were included to which the answers were
contained in the section ‘Take special care with X/Warnings and precautions’. Participants using leaflets with
QRD template 7.3.1 consistently provided significantly the most wrong answers in comparison to the other
two tested templates as participants had noted that they had to take special care but not known how this
should be undertaken i.e. talk to a doctor (tables 46 and 47). This phenomenon has been seen in a previous
study52
. Although the model template used in the readability test in this study provided significantly the most
correct answers for information requested in this section for short text versions of the package leaflet, the new
heading since QRD template 8 can be seen as providing a significant improvement in comprehensibility in
the QRD template in comparison to QRD template 7.3.1, leading to safer use of the medicine. The additional
mandatory statement to talk to a doctor or healthcare professional if a specific situation is present before
taking the product also provides patients with clear instructions. The annotated template of versions 8 and 950
advises MAHs to repeat this advice after each warning/precaution in case of a long-bulleted list - however,
this would again lead to an unnecessary increase in the number of words; particularly as the results of both
warnings and precautions questions of this study showed in the case of the long and short template versions
that such repetition is expendable (tables 46 and 47). Wrong answers regarding what to do in the case of a
kidney transplant were caused by participants providing the dosage instructions for reduced kidney function
which were given in section 3 rather than the advice in the warnings and precautions section.
A further change from QRD template version 8 was the elimination of the terms ‘if you’ or ‘when’ to start the
bullet points in the contraindication and warnings/precautions sections. These terms were also not included in
the tested model template. The results from this study with QRD template 8 and the model template, and a
previous study with the model template52
, show that these words are not necessary and that the information
162
can be provided simply under each bullet point which moves key messages in close proximity to each bullet
point.
Previously QRD template 7.3.1 had included the term ‘hypersensitive’ which was correctly deleted since
QRD template 8 as a hypersensitivity, for example, to the excipient lactose does not automatically lead to
a contraindication189
. This must therefore be welcomed as an improvement in the template. However this
deletion of the word ‘hypersensitivity’ in the package leaflet and retention of this term in the SmPC leads
to an inconsistency between the texts intended for package leaflets and SmPC. This goes against the ruling
in Article 59 of Directive 2001/83/EC as both package leaflet and SmPC must be in accordance with each
other39
.
The analysis of package leaflets downloaded from the EMA website revealed that not all MAHs were of
the opinion that ‘hypersensitivity’ should be deleted and over 20 % of the examined leaflets in the second
and third download with QRD template 8 or 9 still retained both terms. In the third download, there was
also a reduction in the percent of package leaflets which only used the term ‘allergic’ in comparison to the
second download. The use of both terms, and the previously mentioned reduction in use of the term
‘allergic’, maybe due to the fact that the SmPC in QRD template versions 8/9 still retains the term
hypersensitivity and MAHs want to conform to Directive 2001/83/EC and retain conformity between the
package leaflet and the SmPC.
Excipients mentioned in the Excipients Guideline94
are not only listed at the end of the leaflet, but
additionally under a separate heading at the end of section 2 which was the longest heading in QRD
template 7.3.1. The wording of this heading, ‘Important information about some of the ingredients of X’ has
previously been shown that although it attracts attention due to its length, to cause confusion186
and has led
to the belief that the name of the active substance is described here52
. It was recommended that as this
section often only contains one ingredient such as lactose, thereby making it interesting only to those who
are hypersensitive to lactose, that it should be changed to ‘X contains lactose’. Since QRD template 8, this
change has been implicated, but the results of this study show that this did not increase the participants
understanding of whether they can take the medicine if they are allergic to lactose (table 44). In fact, the
question ‘Can you take this medicine if you are allergic to lactose?’ showed the fewest correct answers in
the study. In general, this tested information was usually misunderstood for leaflets with QRD template
7.3.1 or 8 and ‘not found’ for leaflets with the model template. The warning as stipulated by the Excipients
Guideline was mostly the cause of the comprehensibility problems94
. It was commonly thought, that the
medicine could be taken if the doctor was consulted, therefore, the wording for this phrase should perhaps
be reconsidered. The model template demonstrated that an extra subheading for lactose and the warning
163
statement are perhaps unnecessary in future versions of the QRD template. A further alternative would
therefore be to delete the extra excipients warning and statement at the end of section 2 and integrate the
information into the paragraph describing warnings and precautions.
The heading in the QRD template regarding taking the medicine with food and drink was found in readability
studies by Andriesen involving QRD template 7 to cause confusion as readers believe this section will tell
them when to take their medication; before or after a meal, with or without water186
. It is however explicitly
mentioned in the explanatory text in QRD template 8 that such information should be listed in section 356
.
Since publication of QRD template 8, the term alcohol can be optionally added to the ‘Taking X with food
and drink’ heading. This caused a significant reduction in the number of not found answers for leaflets with
the long text version regarding taking the medicine with alcohol (table 50). However, the results also
demonstrate that use of the additional term ‘alcohol’ in package leaflets with QRD template 8 did not cause it
to be superior to the leaflets without this term. The short, clear subheading used in the model template again
provided evidence that a good heading/subheading does not have to be long to increase comprehensibility or
locatability of information, but rather that the information contained under a specific heading/subheading
must be comprehensible.
The heading ‘Driving and using machines’ was identical in all template versions of the leaflet. The volume of
text under this heading may have influenced the fact that participants with the long BfArM text had more
difficulty in finding a reason why their ability to drive maybe affected. This result is similar to that of the
previous question relating to alcohol (table 45). Common incorrect answers relating to driving were caused
by the BfArM text itself rather than the template as subjects had simply written ‘start of treatment’ or ‘dose
increase’ which although not false is not a reason why ability to drive may be reduced, but were explanations
contained in the section.
Information on pregnancy and breast-feeding was provided in model template leaflets in the special
warnings or contraindications sections only. The percentages of correct answers to two questions relating
either to use during pregnancy or breast-feeding showed no significant advantage of any template version
independent of whether this information was repeated in a separate QRD template paragraph or not (tables
42 and 43). As there were no significant differences found to the model template, integrating this
information into the existing section can be recommended which has been identified in previous
studies52,53,60
. The investigation into templates used in other countries also revealed that the Australian
CMI template contains no separate pregnancy, breast-feeding or fertility sections but information
regarding these situations is contained within the contraindication or warnings section which was also
shown to be sufficient according to the results provided in tables 42 and 43.
164
Description of interactions between medicines in the package leaflet are considered by patients to be ‘very
important’ although the location of these interactions should be placed somewhere near the middle of the
package leaflet12,200
. In package leaflets with the model template or QRD template 7.3.1, medicine name and
a description of its use were separated by a colon, whereas for QRD template 8 a description of the
medicines actions was closed in brackets according to the recommendations in the annotated template
version. This was found not to affect the number of correct answers, therefore strictly abiding by the
convention in QRD templates version 8/9 is unfounded and not necessary. Participants who had read the
long BfArM version of the leaflet found it difficult to locate a medicine used to treat heart rhythm disorders
which can influence Enal (table 48), a problem which was probably due to the volume of text in the
interaction section reducing the chance of finding information, which has been seen previously55
. A
negative influence of the template wording is unlikely as the short text version in both languages showed
better results. Conform to the BfArM sample text, the name of the medicine used to treat heart rhythm
disorders was only in the section ‘Take special care/warnings and precautions’ rather than in ‘Taking other
medicines/Other medicines and Enal’ thereby increasing difficulty in finding as participants probably
expected such information in the interaction section. This result again demonstrates the importance of
locating information under the relevant heading/subheading, and that an additional repeat of information
regarding interactions should not be mentioned in the warnings and precautions section, as patients do not
expect to find such information at this location.
A question was also used in the study in which participants had to identify what they should do if they were
already taking a medicine to reduce blood sugar levels (table 49). This information was always contained in
the interaction section of the package leaflet. No significant differences were found between any template
versions and therefore it was shown again that alternative use of colons instead of brackets did not affect the
number of correct answers regarding medicine interactions. The number of correct answers provided for all
template versions with the long BfArM text was generally much higher than for the question regarding
interactions with a medicine to treat heart rhythm disorders, again demonstrating that it is vital that
information is always contained in the appropriate section to aid locatability.
QRD template 8 implemented an extra subheading in section 2 for ‘children and adolescents’ for when a
medicine is indicated in children and this subheading was therefore used in leaflets with this template
version for this study. All leaflets contained information regarding treatment in children in the dosage
section (section 3). The long versions of the BfArM text also always provided information in section 2 of
the package leaflet as this was present in the sample text from BfArM. The results provided in table 51
show that this heading is superfluous regarding finding what indication the medicine is used for in children
165
as there were no significant differences found between leaflets which contained this subheading in section
2, and those which only contained information in section 3. A single subheading is sufficient for finding this
information as long as all relevant information is summarised and present at a single location.
This heading however when provided as ‘children and adolescents’ is rather ambiguous as no statement is
made on which age ranges are affected. Addition of ages in the heading, as was used in all package leaflets
with the model template, would be more helpful as the user can judge who is affected by the content of the
section. Addition of the term ‘adolescent’ is also superfluous according to the definition of children by the
EMA where children are defined as ‘people from birth up to 18 years of age’ meaning that adolescents also
fall within this category203
.
5.5.4 Comprehension and location of information in section 3 of the QRD template for the
package leaflet
Clear and precise dosage instructions are essential to a patient for correctly using medicines. Dosage
instructions and application error tips are considered by patients to be ‘very important’ in the package
leaflet12
. However, whereas patients consider that dosage instructions should be present at the start of the
leaflet, application errors should be placed nearer the end12,200
. Dosage instructions given in active substance
quantities rather than number of tablets have been shown to cause difficulties in patient understanding53
with
up to 90 % of patients not understanding dosage instructions in milligrams of active substance204
. In this
study, the short text versions of the leaflet described the starting dose in amount of tablets while the long text
version from BfArM gave the dose in milligrams of active substance. The results in this research project
(table 52) are supported by the mentioned study as participants found describing the starting dose more
difficult when the quantity of active substance was provided in the package leaflet, as more correct answers
were given with the short text leaflet versions when compared to the long BfArM text versions. Although
both milligrams and number of tablets were considered as correct answers, participants who had read the long
BfArM texts always attempted to provide their answers in milligrams rather than the equivalent number of
tablets. Therefore the QRD template should enforce that only numbers or the volume of a ready to use
medicine, such as number of tablets, are described rather than active substance amount.
The subheading ‘duration of use’ was included in all package leaflets except for the long text version with
QRD template 7.3.1 as the BfArM sample text did not include it. This probably accounted for the
significant difference between the model template and QRD 7.3.1 with regard to the number of not found
answers (table 56). The annotated version of the QRD template 9 suggests including specific information
with regard to duration of treatment which should be based on section 4.2 of the SmPC but no subheading
is recommended. This study however showed that a subheading is beneficial. The shorter leaflet versions
166
provided more correct answers than the long BfArM leaflet versions as although in each leaflet
participants were told that duration of use is determined by the doctor, the BfArM text for enalapril
additionally included the fact that the medicine is usually for long term use. Participants had therefore
noted that the medicine is for long term use but not correctly that the duration of use is determined by a
doctor. Statements such as ‘längere Anwendung’ (long term use) have been shown in a previous study to
be non-quantifiable wording which does not aid the patient in estimating the correct time interval for
taking the medicine or importance of the information60
, which is also seen in the results of this study.
The QRD templates 7.3.1 and 8/9 include a subheading in section three for forgotten use of the medicine
under which the standard statement ‘do not take a double dose to make up for a forgotten dose’ is
contained48,49,51
. The model template included the additional information ‘but continue taking the medicine as
prescribed’. The statement in the QRD template seems not to provide clear advice for the patient as the most
correct answers on what to do in case of a forgotten dose came from the model template (table 53), indicating
that the sentence in the QRD template should possibly be supplemented with additional information.
The slightly different subheading wording between template versions regarding information on overdose
were found to not cause any significant differences in the number of correct, wrong or not found answers
between template versions, showing that each template version was equivalent (table 54). QRD template
7.3.1 and 8 both contained the same heading in the long BfArM text versions for when a patient wants to stop
taking the medicine. There is therefore no explanation for the significantly more correct answers for QRD
template 8 in comparison to QRD template 7.3.1 (table 55).
5.5.5 Comprehension and location of information in section 4 of the QRD template for the
package leaflet
Informing users about the risk of side effects from their medicines is vital if they are to be able to make
informed decisions about their medicine taking183
. However, studies have shown that patients who have
read the package leaflet are more likely to relate health problems which could be side effects to the
medicine taken and stop taking it205
. Although this phenomena is not always observed5,206
.
The first Readability Guideline from 199836
described how the frequency of side effects could be
presented using five verbal descriptors accompanied by a defined numerical rate36
. Testing of these
adjectives ‘very common’, ‘common’, ‘uncommon’, ‘rare’ and ‘very rare’ has however shown that they
lead to a significant over estimation of risk207
, as well as significantly reduced intention to comply208
. Use
of just the verbal descriptors has been shown to also cause considerably higher estimated side effect risk
than when a comparable numerical descriptor in the form of a percentage without an adjective is given209
.
167
A study involving the use of verbal descriptors, percentages and natural frequencies (absolute frequencies
which result from observing cases) further supported these results as verbal descriptors alone led to
significantly higher estimations of risk compared to the two other formats210
.
It is however not only laymen who have problems understanding side effect frequencies regardless of how
they are presented, verbal descriptors, numerical or combined, as discussed in the previous paragraph. A
study in Germany in 2013 involving 1000 doctors, pharmacists and lawyers tested whether 20 verbal
definitions of probability could be interpreted numerically by providing the percentage value211
. The
answers provided were compared to the theoretical values in the official BfArM published guidelines from
November 2006, for example, ‘Häufig: weniger als 1 von 10, aber mehr als 1 von 100 Behandelten’118
(common: less than 1 in 10, but more than 1 in 100 patients). Few of the participants could allocate the
correct percentage to the terms ‘Häufig’ (common), ‘Gelegentlich’ (uncommon) or ‘Selten’ (rare) and it
was shown that the possibly of overestimation of the probabilities of side effects is present in groups of
specialists in medicine-related fields211
. The authors concluded that the definitions of frequencies provided
by BfArM do not correspond to the commonplace use of the terms.
A study which investigated the use of three formats for communicating the risk of side effects to patients
found that the use of combined descriptors such as ‘common (affects less than 1 in 10 people)’ was not
unequivocally superior to absolute frequency alone (e.g. less than 1 in 10 people) and that verbal
descriptors (e.g. common) showed deficiencies for conveying side effect risk212
. Participants who had
received information in the absolute frequency format were more satisfied with the information than the
verbal format. A further study also involving three formats for communicating risk showed that the three
different presentations did not differ in their effect on participants interpretations213
. The three risk
expressions tested were: percentages e.g. affects 25 % of people’, frequencies e.g. affects 1 in 4 people’
and combined e.g. affects 1 in 4 people (25 %). The preferred format was however the combined
frequency and percentage risk expression e.g. affects 1 in 4 people (25 %)213
.
The green explanatory text in the annotated QRD templates 8 and 9 states that a combination of verbal
terms and numerical data should be used to describe the frequency of side effects, and that user testing has
shown that double sided expressions such as ‘affects more than 1 in 100 but less than 1 in 10’ (from the
Readability Guideline published in 1998) are not well understood56
. However, data which support this
opinion has not been published by the QRD group. In the current SmPC a double-sided frequency
convention is recommended e.g. ‘common (≥ 1/100 to < 1/10)’67
while the annotated versions of QRD
templates 8 and 9 use a frequency explanation which is closed on one side for the package leaflet e.g.
‘common, may affect up to 1 in 10 people’48
. The side effect frequency explanations are thereby also
168
discrepant with regards to ruling in Article 59 of Directive 2001/83/EC as both package leaflet and SmPC
must be in accordance with each other39
. This point alone requires that the current QRD template must be
amended in the side effect frequency explanation.
Before publication of QRD template 8, the recommended frequency explanation was that published in
2007 by BfArM120
/EMA182
e.g. ‘Common: affects 1 to 10 per 100 users’. The analysis of package leaflets
downloaded from the EMA website showed that the method of describing frequencies of side effects
changed during the examined time period. Initially, the description type from the BfArM
recommendation120
/EMA report182
was greatly favoured by MAHs followed by that since QRD template
850
(‘Common: May occur in up to 1 in 10 users’). Although the frequency description from the
BfArM/EMA remained the most commonly used in the second download, the number of leaflets using this
method decreased while the number of leaflets with the QRD template 8/9 recommendation increased
(table 28) indicating that MAHs followed the recommendations provided by the QRD template.
In the readability test in this study, three methods of describing side effects were used. The model
template used the recommendations from 2007 made by BfArM120
and the EMA182
. These side effect
frequency explanations are in compliance with those recommended for the SmPC and were developed and
successfully tested in a readability test study involving 1105 participants53
. Leaflets with QRD template
7.3.1 used the verbal and numerical text published in 1998 in the first Readability Guideline36
, while
leaflets with QRD template 8 used the descriptors published in the annotated template since QRD template
8 - a side effect frequency explanation for which no evidence has been provided to confirm that it is the
most optimal version. It was found in this study that the double sided frequency explanations used in QRD
template 7.3.1 leaflets caused comprehensibility problems. It was however not found that using double
sided expressions such as that in the model template led to reduced understanding as stated in the
annotated QRD templates 8 and 950,56
.
When participants in this study were asked to identify in which frequency group a side effect belongs if it
affects 5 in 100 people, QRD template 8 frequency explanations showed the worst comprehensibility.
However, an analysis of the wrong answers provided by participants showed that for both QRD template
7.3.1 and 8, the main problem was that the provided numerical explanation could not be assigned to the
correct frequency group. For QRD template 7.3.1 this was maybe because the frequency explanation was
too long and complicated which led to comprehensibility problems. And for QRD template 8, although the
frequency explanations were short, it was poorly comprehensible which mostly led to an undervaluation of
the frequency but also in some cases to an overvaluation. The results of the PAINT3 study investigating
295 package leaflets with 5091 participants back-up these findings relating to inferiority of the current
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QRD template frequency explanation. In the described German study, the EMA side effect frequency
explanations from 2007 used in the model template were found to have a 10 % higher comprehensibility
rate than that in the QRD template since version 8189
. The presented results from the PAINT3 study and
this research indicate that the QRD group is wrong in its general negative opinion relating to using double-
sided frequency expressions. However, it can be postulated that the frequency explanations in the current
QRD annotated template are probably better comprehensible than those published in the Readability
Guideline from 1998, as it is shorter with less complex phrasing52
.
When participants were asked to write down in numbers ‘How many people are affected by a side effect if
it is rare?’, the participants using the model template and QRD template 8 frequency explanations always
provided more correct answers than when using the QRD template 7.3.1 version, although these
differences were not significant (table 58). The results in table 58 therefore do not demonstrate that the
frequency explanations used in QRD template 7.3.1 from the Readability Guideline published in 1998 was
inferior to the other two description methods in this study, or that double-sided expressions were less
comprehensible as shown by results obtained from participants using the model template. The non-
significant result may be caused by a lower number of participants in comparison to the PAINT3 study by
Fuchs et al. published in 2012 whereby 5091 participants were involved52
. In the PAINT3 study, the
double-sided explanations such as ‘common, affects 1 to 10 per 100 users’ showed a significantly higher
comprehensibility rate than the QRD template explanation valid since version 8.
As shown in section 4.7.9 and table 59 of this study, the current QRD template side effect frequency
explanation often leads to an overestimation of side effect frequency by up to a factor of 10, although
overestimation of risk has been found regardless of the manner of presentation214
. When subjects were
asked ‘How many people are affected by a side effect if it is rare?’, the correct answer would be that it
affects 1 to 10 in 10,000 people, however when participants had read a leaflet with QRD template 8/9 side
effect frequency explanations, nearly all of them believed that a rare side effect generally affected 1 in
1000 people which is the maximum frequency for a rare side effect.
The way of presenting the frequencies of side effects (either as a table at the start of section 4 or as part of
the list) was found in this study not to produce any significant differences between template versions in
the ability of participants to comprehend and locate how many people were affected by a side effect if it
was rare (table 58). Incorporating the frequency descriptions of side effects into the list of side effects
rather than using a table at the start of section 4 for the frequencies however reduces the space needed to
print this section of the package leaflet. Also, using side effect frequencies as subheadings and
subsequently listing the corresponding side effects brings both in near proximity making it easier for the
170
user to read which side effects are listed with a certain frequency. This change in frequency description
has been assessed by other authors as positive189
. Furthermore, the table for side effects was considered by
participants as being unnecessary as it was an element which some participants wished to delete in the
package leaflet (table 73).
The Readability Guideline from 199836
suggested dividing side effects into ‘serious’ where medical advice
should be sought immediately, and ‘less serious’ which is also recommended since QRD template 9. The
wording used is important as testing of the terms ‘immediately’ and ‘as soon as possible’ has shown not to
be interpreted differently, although the meaning of the two terms is very different215
. Some side effects
such as severe allergic reactions require ‘immediate’ medical attention, whereas a doctor can be consulted
at the patients’ convenience (‘as soon as possible’) for other side effects, indicating that clearly worded
statements and actions to be taken are vital. The side effect section was structured differently in this study
for each version of the leaflet whereby leaflets with QRD template 8 followed template recommendations
and presented the most serious side effects first, the model template had serious side effects printed in bold
and leaflets with QRD template 7.3.1 listed ‘countermeasures’ at the end of section 4 for serious side
effects. When participants in this study were asked to locate a serious side effect where they should
immediately contact their doctor, there were no significant differences between the number of correct or
wrong answers provided between template versions. However, for the long BfArM text versions, the
model template provided significantly more not found answers that either QRD template, indicating that
using bold type in the model template was inferior to listing severe side effects first which is suggested in
the QRD template since version 8, or having a separate section for countermeasures (table 62).
Knowing how to take appropriate actions is important if any side effects should occur, but the wording in
QRD template 7.3.1 led many patients in this study to believe that a healthcare professional should only be
contacted ‘If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet.’
This has also been seen in other studies52,53
. QRD template 8 provided the most correct answers (table 61).
Generally recommending contacting a doctor if side effects occur reduced misunderstanding and can
therefore be welcomed as an improvement.
The new subheading in section 4 of QRD template 9 ‘Reporting of side effects’48
and the mandatory text
whereby patients are actively encouraged to report any occurring side effects was caused by the
pharmacovigilance legislation implemented in 201342
. The text extension cannot be seen as positive as the
word count of mandatory text in the side effect section of QRD template 9 is increased by three times in
comparison to its predecessor and it cannot be excluded that this will reduce the usability of the provided
instructions48,49
. The supposition that medical laymen can differentiate between side effects caused by a
171
particular medicine rather than symptoms caused by other factors such as the particular condition itself
must also be considered critically216
. Moreover, using package leaflets for other purposes such as reporting
side effects deviates from their intended function of informing patients on proper use of their medication.
5.5.6 Comprehension and location of information in section 5 of the QRD template for the
package leaflet
Storage information was always contained under the same heading in section 5 of the leaflet for all
versions. This information is considered by patients to be ‘important’ and it is considered that it should be
located at the end of the leaflet12,200
. The shorter message contained in the model template regarding
keeping the medication inaccessible to children proved sufficient as no significant differences were seen
between template versions (table 63).
5.5.7 Comprehension and location of information in section 6 of the QRD template for the
package leaflet
In the European Union, the package leaflet is intended for use by the patient whereas the SmPC is
designated for specialist use. This separation of medicinal information was intended to make the package
leaflet more patient-orientated. However, since publication of QRD template version 5 a separate heading
was provided at the end of section 6 for information for healthcare professionals. Around 24 % of leaflets
from each download of package leaflets from the EMA website contained information for healthcare
professionals, which in some cases accounted for over 50 % of the total words (table 26). Although it has
been shown that specialists use patient information as much as patients12
, this study demonstrated that the
volume of text is greatly increased by this information. In view of the fact that a SmPC is available for
professionals, care should be taken by MAHs in the amount of professional information which is included
in the patient leaflet.
The QRD template for centralised procedures makes provision for a list of 30 names and addresses of
local MAH representatives. Although inclusion of this list is non-compulsory, over 80 % of the examined
leaflets in each download of package leaflets from the EMA website contained this list which contributed
to up to 33.6 % of the total text volume. According to the readability test results provided in table 73, this
list was the most frequent aspect of the package leaflet which participants would delete. As increasing the
number of words is a major factor in decreasing patients’ motivation to read the leaflet and their ability to
locate information55
, omission of this list should supported, especially as it does not offer any medicine
specific information, contributes to the text volume and is little importance for patients or healthcare
professionals. Additionally, limitations of spoken languages make it unlikely that patients would contact
172
foreign representatives, and QRD template version 3 also does not recommend such a list for non-
centralised approved medicines. Furthermore, this information can be reduced to only the relevant local
representative and not the entire list of local representatives. This change will be implemented in a revised
version of the QRD template which will include this guidance (personal communication, EMA 2014).
5.5.8 Comprehension and location of information regarding tablet divisibility
When specialists were asked what information should be contained in a package leaflet, it was stated that
information outlining tablet divisibility should always be present12
. Divisibility can be described verbally
or by using a pictogram or both. Patients are often presented with a tablet with a score line which could
cause confusion as a score line does not always mean that a tablet can be divided into equal doses but
rather than two halves are easier to swallow than a whole. The annotated version of the QRD template 8
took this into account and included three optional statements regarding divisibility.
As QRD template 8 included the optional statement ‘this tablet can be divided into equal doses’ this
sentence was included in package leaflets used in this readability test study with this template. Leaflets
with the shortened text version all contained a picture of the tablet being divided which probably
accounted for the fact that over 97 % of participants could answer the question correctly as to whether the
tablet could be divided. With the long BfArM text version, leaflets with QRD template 8 provided
significantly the most correct answers showing that the statement regarding divisibility is essential (table
65). The other two leaflets with the long BfArM text version contained neither statement nor picture
regarding tablet divisibility. The picture showed better results in the location and understanding of the
provided information in comparison to the statement as in leaflets with QRD template 8, as was
demonstrated by the results from the short leaflet versions.
5.5.9 Effects of demographic factors on participants ability to comprehend and locate information
It has been shown that elderly people and those with a low level of academic education have particular
difficulty in finding and understanding medical information in package leaflets with older readers also
needing more time to locate information217
. In the study described in this work, readers in Germany who
were older than 60 needed the longest time to answer the questionnaire in the readability test whether a
longer or shorter text had been read with youngest participants being the fastest (table 75). In England
however, participants who were over 60 were fastest reading the short leaflet. Influences of the age
structure present in the English subject group may account for this result. A further similar study has
shown that as age increased, that the time taken to locate and provide requested information was
increased53
.
173
Participants who had only completed education to the 8th class provided the least correct answers although
this was not significant (table 77). For all other education levels no significant differences were found
which indicated that a higher education level had led to better understanding of the leaflet. The number of
medicines participants took each day also did not influence the number of correct answers provided (table
76) as has been previously seen in a similar study53
.
5.6 Global aspects relating to the QRD template
The analysis of the number of words in the QRD template from the initial publication to the present day
showed that both the minimum and maximum number of words contained in the template has steadily
increased which thereby plays a role in the increasing text volume in package leaflets. The QRD template
9 published in March 2013 showed a further text increase due to additional text elements based on the new
EU pharmacovigilance legislation which is intended to increase patient safety when using medicines24,25
.
The analysis of package leaflets available on the EMA website for centralised approved medicines showed
that pharmaceutical companies use up to 67.3 % the QRD template 9 text (565 of the possible maximum
840 words in this template version). As the maximum possible number of words contained in each version
of the QRD template was never used in the examined package leaflets, it would seem that MAHs often
follow, at least partially, the bracketing convention and do not use the QRD template in its entirety.
Chapter 4.6.3 of this research shows that between an average of 19.7 % and 21.5 % of the text in each
leaflet was caused by the QRD template depending on template version, with implementation of the actual
template version 9 causing the greatest average percent of template words (tables 25 and 26). The results
show that with each new edition of the QRD template the average number of words in the package leaflet
caused by this template increased by more than 10 %. However, both patients and healthcare professionals
strongly favour more concise package leaflets1,12
and it has also been shown that increasing the number of
words used in package leaflets significantly decreases patients’, motivation to read the package leaflet,
reduces trust in using the medicine plus the ability to locate the provided information is impeded55,218
.
When assessing readability of package leaflets, a correlation has been found between the number of words
and poor or good readability. Package leaflets which motivated patients to read them, increased
confidence in the medicine and with good readability regarding ease of location of information were found
to have less than 1500 words218
. This again shows the importance of keeping package leaflets as concise as
possible which must also take the length of the QRD template itself into consideration.
The latest versions of the template have led to the introduction of the optional use of the terms ‘patient’ or
‘user’ at the top of the leaflet. This choice is not necessary advantageous as the term ‘user’ could simply
be written rather than trying to take into account everybody who might read the leaflet. A further fault of
the template from version 3 onwards in English is the heading at the top of the template. The term
174
‘Package leaflet’ could be unclear as in the UK the term ‘Patient information leaflet’ is commonly used101
.
Implementation of pharmacovigilance legislation in QRD template version 9 caused the introduction of a
black inverted triangle to identify products which are subject to additional monitoring43
. The presence
however of a black symbol and statement that the medicine is ‘subject to additional monitoring’ may
cause patients to be put off taking a medicine as they consider it unsafe216
and cannot be assessed as
positive.
Additional use of other optional terms has been introduced in the most recent versions of the template for
example ‘nurse’ in some sections where previously only the terms ‘doctor and/or pharmacist’ were listed,
‘alcohol’ in the subheading of the section for interactions with food and drink, and ‘fertility’ in the section
subheading for pregnancy and breast-feeding. Use of these additional terms further contributes to the text
volume. Information on fertility does also not have to be described for each medicine according to
Directive 2001/81/EC Article 59, 1 (c)39
. The study of the package leaflets for centralised approved
medicines showed that too little thought is frequently given by MAHs and agencies when using the
optional terms ‘fertility’ in the heading for pregnancy and breast-feeding and ‘alcohol’ in the section for
interactions with food and drink (section 4.6.8). The situation was seen that over 25 % of package leaflets
which used the term ‘fertility’ in the subheading of the second and third downloads contained no
information regarding fertility and around 10 % of package leaflets in the second and third downloads
which used the term alcohol in the subheading had no information on alcohol, meaning that these terms
were superfluous, a fact which maybe MAHs should be made aware of. A further example of suboptimal
use of the template was seen regarding the optional standard sentence present under the subheading
‘Pregnancy and breast-feeding’. Although in the minority, several package leaflets contained the wording
for this sentence from both template versions 7 and 8/9, thereby causing an unnecessary increase in text in
this section, perhaps as deletion of the previous text version had been overseen. The analysis of package
leaflets for centralised procedures also demonstrated that a large number of package leaflets were only
partially adapted to the QRD template, for example, with regard to the standard warning statement for
interactions with other medicines. The situation was seen in download three, that 21.4 % of the package
leaflets with QRD template 8/9 still retained the statement from QRD template 7.
The QRD template contains numerous repetitions although this is advised against in the readability
guideline38
as it leads to text redundancy and causes unnecessary increases in text volume. For example,
the name of the active ingredient is repeated three times in the template since publication of QRD template
8, and the information that a patient must contact a doctor if side effects occur is contained in the
information box at the start of the leaflet and at the end of section 4 with identical wording. The results of
the readability test in this study showed that repeating the name of the active ingredient is redundant in the
175
template and it is sufficient to simply list it along with the list of other ingredients. This multiple repeat
should therefore also be eliminated in the template. The model template used in this study contained no
information box and the advice sentence if side effects occur was contained at the end of section 4. QRD
template 8 provided significantly more correct answers than the model template for short text versions in
England and the long BfArM text versions (table 61), however the wording used for each template
differed which may have led to the differing comprehensibility rather than the fact that the information
was not contained at the start of leaflets with the model template. A separate section for pregnancy and
breast-feeding also causes a repeat of information and as the model template without a separate section
showed, integration of this information into contraindications or warnings and precautions is sufficient,
thereby eliminating a further repetition of information.
5.7 Summary of advantages/disadvantages/significant differences between templates
5.7.1 Comparison of QRD template 7.3.1 and 8
A comparison of the results from the readability test revealed that package leaflets with QRD template 8
was mostly superior to those with QRD template 7.3.1 in terms of comprehensibility for long and short
text versions in both languages (table 78) showing that QRD template 8 had improved readability in
comparison to its predecessor. More correct answers were provided with QRD template 8 which could be
influenced not only by the fact that the information was more comprehensible, but that the increased
comprehensibility made it easier to find. The subheading ‘warnings and precautions’ in QRD template 8
rather than ‘take special care with X’ in QRD template 7.3.1 led to better comprehensibility and
locatability of how to act in the case of a kidney transplant or when a dental operation is needed. It was
also demonstrated that QRD template 8 provided better comprehensibility than QRD template 7.3.1 in
section 3 of the package leaflets.
QRD template 7.3.1 used a table preceding the list of side effects to describe the frequencies while QRD
template 8 describes the frequency of side effects as part of the list as subheadings. This method is space
saving and brings the respective side effect in close proximity to the frequency189
. The description method
of side effect frequencies from QRD template 7.3.1 was found to be superior to that from QRD template 8
in terms of comprehensibility for all versions of the package leaflet in both languages. Presenting the side
effect frequencies in a table as in QRD template 7.3.1 perhaps makes this information more visible which
led to more found answers than with QRD template 8.
The statement on how to act if side effects occur from QRD template 8 was more comprehensible and
easier to find than that from QRD template 7.3.1 especially in short versions of the leaflet. The large
number of wrong answers provided by participants who had read versions of the leaflets with QRD
template 7.3.1 were caused by misunderstanding the wording in QRD template 7.3.1 which has also been
found in a previous study53
.
176
The participants’ opinions in England for short versions of the leaflet showed that it was considered that
the subheadings in QRD template 8 were more comprehensible than those in QRD template 7.3.1 and they
were more satisfied with the information provided in package leaflets with QRD template 8. Participants
who had read long BfArM versions of the package leaflet felt that leaflets with QRD template 8 had
provided the better instructions for using the medicine. These results on the subjective opinions of the
participants also demonstrate the superiority in terms of patient satisfaction with QRD template 8.
177
Table 78: Significant differences found in the readability test between QRD template 7.3.1 and QRD template 8
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
QRD
template
7.3.1
QRD
template
8
EN - short
text
DE - short
text
DE - long
BfArM
text
Total of
provided
answers
Total result
x x x x
QRD template 8 more correct
answers due to better
comprehensibility
Table 38
Appendix 13
Comprehensibility x x x x
QRD template 8 less wrong
answers
Table 38
Appendix 13
Package
leaflet
section 2
Better
understanding and
location of
warnings and
precautions
x x x x
QRD template 8 more correct and
less wrong actions in the case of a
kidney transplant*
Table 47
Appendices
14, 15, 16, 17,
18, 19
x x
QRD template 8 less not found
actions in the case of a kidney
transplant
Table 47
Appendix 22
x x x
QRD template 8 more correct
actions if dental operation needed
Table 46
Appendices
14, 15
x x x
QRD template 8 less wrong actions
if dental operation needed
Table 46
Appendices
17, 18
178
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
QRD
template
7.3.1
QRD
template
8
EN - short
text
DE - short
text
DE - long
BfArM
text
Better location of
information on
interactions with
food and drinks
x x
QRD template 8 less not found
answers what should be done with
regard to drinking alcohol when
taking the medicine
Table 50
Appendix 23
Package
leaflet
section 3
Better location of
dosage instruction x x
QRD template 8 less not found
answers for starting dose to be
taken
Table 52
Appendix 22
Better method of
use result x x
QRD template 8 more correct
answers for whether the tablet can
be divided
Table 65
Appendix 16
Better results for
what to do if
desired to stop
treatment
x x
QRD template 8 more correct
answers on how to act if treatment
should be stopped
Table 55
Appendix 16
Package
leaflet
section 4
Better results
understanding side
effect frequencies x x x x
QRD template 7.3.1 more correct
answers for ‘In which of the side
effect frequency groups does the
following frequency: ‘affects 5 in
100 people’ belong?’
Table 60
Appendices
14, 15, 16
179
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
QRD
template
7.3.1
QRD
template
8
EN - short
text
DE - short
text
DE - long
BfArM
text
Better results
understanding side
effect frequencies x x x
QRD template 7.3.1 less wrong
answers for ‘in which of the side
effect frequency groups does the
following frequency: ‘affects 5 in
100 people’ belong?’
Table 60
Appendices
18, 19
Better locatability
of side effect
frequencies x x x x
QRD template 7.3.1 less not found
answers for ‘in which of the side
effect frequency groups does the
following frequency: ‘affects 5 in
100 people’ belong?’
Table 60
Appendices
20, 21, 23
Better results of
how to act in the
case of side effects
occurring
x x
QRD template 8 more correct
answers on how to act if a side
effect occurs
Table 61
Appendix 14
Better results of
how to act in the
case of side effects
occurring
x x x
QRD template 8 less wrong
answers on how to act if a side
effect occurs
Table 61
Appendices
17, 18
180
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
QRD
template
7.3.1
QRD
template
8
EN - short
text
DE - short
text
DE - long
BfArM
text
Better locatability
of how to act in the
case of side effects
occurring
x x
QRD template 8 less not found
answers on how to act if a side
effect occurs
Table 61
Appendix 20
Better locatability
of the frequency of
a specific side
effect
x x
QRD template 8 more correct and
less wrong answers for ‘how
frequent is the side effect ‘hair
loss’?’*
Table 57
Appendices
16, 19
Partici-
pants
opinion
Subheading
wording x x
QRD template 8 more favoured for
statement ‘each subheading
clarifies the information contained
in the following section’
Table 66
Comprehensibility
x x
QRD template 8 more favoured for
statement ‘’the content of this
package leaflet was easy to
understand’
Table 67
181
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
QRD
template
7.3.1
QRD
template
8
EN - short
text
DE - short
text
DE - long
BfArM
text
Satisfaction with
provided
information x x
QRD template 8 more favoured for
statement ‘I feel well informed
from the information contained
within this package leaflet’
Table 68
Satisfaction with
provided
information x x
QRD template 8 more favoured for
statement ‘this package leaflet
provided all the instructions I
needed to use the medicine’
Table 68
Number of
siginif-
icant
advantages
for:
QRD template
7.3.1
-
2 3 3 Total result: QRD template 8 is
superior to QRD template 7.3.1
with the exception of the side effect
frequency explanation
-
QRD template 8
11 7 13
EN = English, DE = German
* If significantly more correct and less wrong answers were found, this result was counted twice
182
5.7.2 Comparison of model template and QRD template 8
Comparing the results of the readability test between QRD template 8 and the model template revealed
that the model template was more comprehensible in terms of providing more total correct answers and
less wrong answers than QRD template 8 for short text versions in both languages (table 79). However,
the model template was significantly better than the QRD template 8 in terms of the time needed to find
the requested information for long BfArM text versions. Package leaflets using the model template
contained more than 1000 words less than the package leaflets with the QRD templates which most likely
accounted for this result. Information was also presented under clearer, shorter headings.
Further advantages of the model template were also seen several times with regard to understanding
warnings and precautions located in section 2 of the package leaflet. However, QRD template 8 was
superior once to the model template in terms of locatability of information for long BfArM text versions
with respect to how to act in the case of a kidney transplant.
When participants were asked in which side effect frequency group the frequency ‘affects 5 in 100 people’
belongs, the comprehensibility and locatability of this information was superior for the model template
compared to QRD template 8 for all package leaflet versions as already discussed in section 5.5.5. The
description method of frequencies from QRD template 8 has previously been shown to be less
comprehensible189
and causes an important overestimation of side effect frequency.
The sentence from QRD template 8 instructing participants on how to act in the case of side effects
occurring was superior to that from the model template in terms of comprehensibility and locatability.
The QRD template 8/9 requests that most serious side effects are listed first corresponding to the
recommendations of the Readability Guideline from 200938
. Describing most serious side effects first
showed an advantage for the QRD template 8 in comparison to the model template for long BfArM text
versions. Participants who had read long BfArM text versions with QRD template 8 provided significantly
more correct answers than with the model template when asked to locate the frequency of the side effect
hair loss. This could however be due to the fact that the model template provided the information in the
second column of the page rather than the first, as in QRD template 8. It has been shown in a previous
study that page breaks and column changes within a chapter reduce locatability of information53
. However
in all 6 short versions of the package leaflets there was a page break within chapter 4 which did not reduce
locatability of the side effect. This page break was at the same position in all leaflets and the text versions
were significantly shorter and optimised. Additionally, the side effect ‘hair loss’ was at the start of the
bullet point in all short text versions which most likely led to more correct answers through better
locatability.
The model template motivated more the participants to read the leaflet in comparison to QRD template 8,
led to more confidence in the medicine, and participants were more satisfied with package leaflets using
this template than those with QRD template 8. A previous study has shown that increasing text volume
183
reduces motivation to read the leaflet and reduces confidence in the medicine53
which supports the results
shown here, as the shorter leaflets with the model template provide more motivation to read the leaflet.
The results thereby show that the model template was in many aspects superior to QRD template 8,
although for long BfArM text versions, the QRD template 8 increased the percentage of located
information, but also increased the locatability time.
184
Table 79: Significant differences found in the readability test between the model template and QRD template 8
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
Model
template
QRD
template 8
EN - short
text
DE - short
text
DE - long
BfArM
text
Total of
provided
answers
Total result x x x
Model template more correct
answers
Table 38
Appendix 13
Comprehens-
ibility x x x x
Model template less wrong answers Table 38
Appendix 13
Locatability x x
QRD template 8 less not found
answers
Appendix 13
Time
Time taken to
find requested
information
x x
Using model template needed
significantly less time to find
requested information
Table 37
General
inform-
ation
Better locatability
of whether the
medicine
available on
prescription
x x
QRD template 8 less not found
answers for whether medicine is on
prescription or not
Table 39
Appendix 21
Package
leaflet
section 2
Warnings and
precautions x x
Model template significantly more
correct answers on how to act in the
case of lactose allergy
Table 44
Appendix 14
x x x x Model template significantly less Table 44
185
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
Model
template
QRD
template 8
EN - short
text
DE - short
text
DE - long
BfArM
text
wrong answers on how to act in the
case of lactose allergy
Appendices
17, 18, 19
x x x x
QRD template 8 significantly less
not found answers on how to act in
the case of lactose allergy
Table 44
Appendices
20, 21, 23
x x
Model template significantly more
correct answers if dental operation
needed
Table 46
Appendix 14
x x
Model template significantly less
not found answers if dental
operation is needed
Table 46
Appendix 20
x x
Model template significantly less
wrong answers in the case of
kidney transplant
Table 47
Appendix 19
x x
Model template significantly less
not found answers in the case of
kidney transplant in short text
version
Table 47
Appendix 20
186
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
Model
template
QRD
template 8
EN - short
text
DE - short
text
DE - long
BfArM
text
x x
QRD template 8 significantly less
not found answers in the case of
kidney transplant in long BfArM
text version
Table 47
Appendix 22
Package
leaflet
section 3
Better
comprehension of
method of use
x x
QRD template 8 significantly more
correct answers for whether tablet
can be divided
Table 65
Appendix 16
Package
leaflet
section 4
Better
comprehension
and locatability of
side effect
frequencies x x x x
Model template significantly more
correct answers, less wrong
answers and less not found answers
for ‘in which of the side effect
frequency groups does the
following frequency: ‘affects 5 in
100 people’ belong?’*
Table 60
Appendices
14, 15, 16, 17,
18, 19, 20, 21,
23
Better results of
how to act in the
case of side
effects occurring
x x x
QRD template 8 significantly more
correct answers on how to act if a
side effect occurs
Table 61
Appendices
14, 16
187
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
Model
template
QRD
template 8
EN - short
text
DE - short
text
DE - long
BfArM
text
Better results of
how to act in the
case of side
effects occurring x x
QRD template 8 significantly less
not found answers on how to act if
a side effect occurs
Table 61
Appendices
20, 23
Better
comprehension
and locatability of
the frequency of a
specific side
effect
x x
QRD template 8 more correct
answers and less not found answers
for ‘how frequent is the side effect
‘hair loss’?’*
Table 57
Appendices
16, 22
Better locatability
of how to act in
the case of a
severe side effect
x x
QRD template 8 significantly less
not found answers on which side
effects require immediate contact
with a doctor
Table 62
Appendix 22
Partici-
pants
opinion
Motivation to
read the leaflet x x
Model template favoured for
statement ‘the first impression of
this package leaflet motivated me to
Table 69
188
Item Subitem Significant advantage
for
Which text versions showed
significant differences
Comment Reference
Model
template
QRD
template 8
EN - short
text
DE - short
text
DE - long
BfArM
text
read further’
Confidence in the
medicine x x
Model template favoured for
statement ‘the content of this
package leaflet does not raise my
concerns about using this medicine’
Table 70
Satisfaction with
the package
leaflet x x
Model template favoured for
statement ‘Would you like all
package leaflets to be similar to this
one?
Table 70
Number of
significant
advantages
for:
Model template
-
10 7 9 Total result: The model template
was superior is many aspects to
QRD template 8 especially for short
text versions of the package leaflets
tested
-
QRD template 8
3 2 8
EN = English, DE = German
* If significantly more correct, less wrong answers and less not found answers were present, this result was counted three times, or if significantly
more correct and less wrong answers were found, this result was counted twice
189
5.8 Future perspectives to improve the QRD template
Although providing no specific information regarding using a certain medicine, the analysis of package
leaflets of centralised approved medicines showed that the ever expanding volume of the QRD template
contributes to the volume of text increase in the package leaflet. The readability test study performed in
this work has additionally shown the significant advantages of a shorter model template in comparison to
both tested versions of the QRD template for a long leaflet text, with respect to less time needed to locate
content (table 37), and more correct answers for short versions of the package leaflet in two languages
(table 38). Keeping the QRD template concise should therefore be a priority of future versions of the
template, particularly as the model template was not inferior to the current QRD template. Until use of a
shorter QRD template becomes reality, MAHs should also be made aware of the fact that comprising the
QRD template text by strictly applying the bracketing convention and avoiding repetitions can reduce the
text volume by 20 %55
.
Use of the model template revealed that certain elements are not necessary in the QRD template and could
therefore be omitted to reduce text volume. Even though the QRD template states ‘user testing to date has
indicated that most patients value a content listing in the package leaflet’49
, an index is not essential
according to the results of this study whereby the model template was not inferior to two template versions
with a contents list. Two other studies with the model template confirm these findings52,53
. Other
investigated available templates from non-EU countries also do not contain a contents list demonstrating
that future versions of the template could maybe place the contents list in pointed brackets making it
optional according to the type of leaflet - for a booklet, an index is useful for locating information.
Furthermore, the model template did not include an information box at the start of the leaflet. This
information box provides several duplications which are found in other sections and was only a
component of the template for the package leaflet in Switzerland, otherwise none of the examined
countries contained an information box. The results of this study again showed that the information box is
not necessary and should be deleted.
The model template strictly avoided repetitions, such as including an extra section for pregnancy and
breast-feeding, and multiple repeats of the name of the active substance which reduced the length of the
template text. The results comparing both QRD templates 7.3.1 and 8 to the model template illustrate that
repetitions do not improve package leaflets. There were no significant differences in the number of correct
answers between the model template and QRD template versions which contained a separate section for
pregnancy and breast-feeding, demonstrating that repeating this information was not beneficial.
190
Participants using the model template provided significantly more not found answers than either QRD
template when they were asked how to act if they were allergic to lactose. However, the apparent benefit
of the separate subsection in the QRD templates was counteracted by the fact that the participants
significantly misunderstood the wording from the Excipients Guideline94
which means that all three
template versions require improvement. One suggestion would be to integrate the Excipients Guideline
warnings under the ‘Warnings and precautions’ heading and emphasise and/or reword the contraindication
bullet point as following:
‘Do not take X in the case of
• allergy to any ingredient of X listed in section 6’.
However, before this suggestion could be implemented, user testing is required.
Participants using the model template and QRD template 7.3.1 provided significantly more correct
answers for the question ‘in which of the side effect frequency groups does the following frequency:
‘affects 5 in 100 people’ belong?’ demonstrating that this method of describing side effect frequencies was
superior from both these templates compared to QRD template 8. The frequencies in QRD template 8 also
led to an overestimation of frequency. These results show that a rewording of the side effect frequencies is
necessary to the version recommended by the EMA182
and BfArM120
in 2007 for future versions of the
template as it shows significantly better comprehensibility and is in line with the recommendations for the
SmPC67
.
The fact that participants who had read the long BfArM text frequently provided less correct answers than
the shorter text versions was often due to the wording in the BfArM text and was not dependent on the
template used. This is a prerequisite which exists in general, that to be able to comprehend and locate
information, that the information itself must be present and comprehensible and located under the correct
heading/subheading. This was demonstrated for example by the question as to whether the tablet can be
divided - this information was missing in the package leaflet version with the BfArM text; therefore both
the model template and QRD template 7.3.1 provided worse results than QRD template 8 (table 65).
The question therefore arises of whether we need a shorter template if QRD template 8 is already better
than 7.3.1 or comparable to the model template? For short versions of the package leaflet the model
template was definitely superior in terms of the number of correct answers. For long BfArM versions of
the leaflets the time needed to answer the content questions was significantly less with the model template
when compared to either QRD template showing that the conciseness was important for time needed to
locate the leaflet information. Additionally, the main two pieces information which were not found in the
model template compared to QRD template 8 in long BfArM text versions were tablet divisibility (as
191
discussed above) and whether the product was available on prescription. The fact that prescription status
of a product is usually a component of the outer packaging, and making inclusion of a standard text or
picture regarding divisibility a necessity in the package leaflet, would however solve both these problems.
What however should be seriously considered is readability testing of new versions of the QRD template
before implementation, especially in the light of findings which show that path taken by the European
Commission in demanding readability testing of package leaflets themselves is suitable for improving
readability.
192
6. Summary
Background: Package leaflets of medicines distributed within the European Union must reflect the QRD
template. Since the first edition of the QRD template from 1996, thirteen revisions have followed. During
development the QRD template update published in 2011, headings and mandatory texts underwent major
changes based on information gained from user testing and feedback from various sources. The methods
and resulting data used to create these amendments remain unpublished.
Aims of the project: This study aimed to analyse the development of the QRD template from its initial
version to the present day and addressed the problem of insufficient data regarding its readability and use.
Content and structure comparison of templates of non-EU countries to the QRD template was another aim.
Materials and methods: The English QRD template text intended for package leaflets of centralised
approved OTC medicines was analysed regarding the number of words, and content of information
contained in each section. In addition, a written readability test was carried out using package leaflets with
QRD templates 7.3.1, QRD template 8 and a model template using three enalapril texts: German BfArM
sample text, and a shortened German version of the BfArM sample text and its English translation. Every
participant tested all three templates with a 6 month time gap in a cross-over procedure. An internet search
was used to identify package leaflet templates available in English and German; the content and structure
of these templates were analysed including the relevant directives and guidelines. To investigate how
widely the QRD template is implemented in the practice, package leaflets for centralised approved
medicines were downloaded from the EMA website three times with a year between each download.
Results: During development of the QRD template up to the present day, the number of words has
increased from initially less than 100 to over 800. The continuous updating has led to wide-ranging
structural and content changes in the template as well as altering the wording of many headings and
standard statements. A total of 241 people from Germany and England participated in the readability test.
For the short leaflet text, participants provided significantly more correct answers with the model template
compared to both QRD templates. For the long BfArM sample text tested in Germany, participants
provided a comparable numbers of correct answers with QRD template 8 and the model template, but
significantly less when QRD template 7.3.1 had been used. Information contained in the sections for
contraindications, precautions and possible side effects caused the most problems with regard to
locatability and comprehensibility. Analysis of the package leaflets for centralised procedures showed that
up to nearly 40 % of the text used in package leaflets can come from the QRD template.
Conclusions: The continuous updating of the QRD template can be seen as positive as improvements
have been found in general headings and standard sentences. Further optimisation is however still possible
by reducing the length of the text and rewording the description of side effect frequencies.
193
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List of tables
Table 1: Elements contained in QRD templates 7 and 8/9 .......................................................................... 13
Table 2: Range for assessment criteria for participants’ opinions on the package leaflet ........................... 20
Table 3: Development of template main section headings to be used in package leaflets .......................... 24
Table 4: Template texts to be used after the name of the medicine and active substances at the beginning
of the package leaflets for OTC medicines (changes in comparison to the predecessor are highlighted in
grey)............................................................................................................................................................. 26
Table 5: Subheadings (in bold) and standard statements (normal type) used in section 2 of the template
(changes in comparison to the predecessor are highlighted in grey) ........................................................... 30
Table 6: QRD template standard statements intended for use in package leaflet section 4 (changes in
comparison to the predecessor are highlighted in grey) .............................................................................. 33
Table 7: Internet sources used to gain information on patient information, template structure and content in
selected countries ........................................................................................................................................ 35
Table 8: Documents influencing the content of the package leaflet in the United Kingdom ...................... 37
Table 9: Documents influencing the contents of the package leaflet in Germany ...................................... 40
Table 10: Documents influencing the content of the package leaflet in Switzerland.................................. 42
Table 11: Documents influencing package leaflets in Australia ................................................................. 45
Table 12: Documents influencing package leaflets in New Zealand .......................................................... 47
Table 13: Summary of consumer information for prescription medications in the United States .............. 47
Table 14: Documents influencing consumer information on medicines in the United States ..................... 50
Table 15: Main headings to be used in the Swiss package leaflet template for prescription and OTC
medicines from AMZV in comparison to headings (bold type) and subheadings (normal print) from QRD
template 9 .................................................................................................................................................... 53
Table 16: Sections headings and subheadings in the Australian core CMI template in comparison to QRD
template 9 .................................................................................................................................................... 58
Table 17: Sections headings and subheadings in the New Zealand core consumer medicine information
(CMI) template in comparison to QRD template 9 headings and subheadings........................................... 62
Table 18: Comparison of the content and order of information contained in the Medication Guide, CMI,
labelling of OTC medicines and the QRD template 9 ................................................................................. 66
Table 19: Comparison of QRD template 9 to templates from Switzerland, Australia, New Zealand and the
USA ............................................................................................................................................................. 68
212
Table 20: Distribution of the analysed 565 package leaflets according to prescription status and
pharmaceutical form of the medicines in the first package leaflet download from the EMA website
including the complete sample of 616 package leaflets .............................................................................. 73
Table 21: Percentage of package leaflets in the first download which were analysed, and the complete
sample of 616 package leaflets downloaded from the EMA website, relating to the anatomical main group
of medicines according to ATC code .......................................................................................................... 74
Table 22: Package leaflets downloaded from the EMA website assessed relating to the presence of
contents list, inclusion of section ‘Reporting side effects’ and points in the information box of the QRD
template ....................................................................................................................................................... 76
Table 23: Percentage of package leaflets downloaded from the EMA website according to medicine type
where point 3 in the information box of the QRD template had been omitted ........................................... 77
Table 24: Percentage of package leaflets downloaded from the EMA website assessed according to terms
used in point 2 of the information box of the QRD template ...................................................................... 77
Table 25: Date of last update of the product information and average number of total words and QRD
template plates contained in the package leaflets of centralised approved medicines downloaded from the
EMA website ............................................................................................................................................... 79
Table 26: Analysis of the number of words contained in package leaflets downloaded from the EMA
website with regard to additional patient text, information for healthcare professionals, QRD template text
for each template version and the address list for representatives of the marketing authorisation holder .. 80
Table 27: Analysis of package leaflets downloaded from the EMA website regarding location of severe
side effects and form of presentation of side effect frequency explanations ............................................... 82
Table 28: Analysis of the method of description of the frequency of side effects in package leaflets
downloaded from the EMA website ............................................................................................................ 83
Table 29: Analysis of the frequency of use of the terms food, drink and alcohol in the subheading ‘Taking
X with food, drink and alcohol’ in package leaflets downloaded from the EMA website .......................... 85
Table 30: Analysis of the pregnancy and breast-feeding advice sentence contained in package leaflets
downloaded from the EMA website ............................................................................................................ 86
Table 31: MAH information presented in package leaflets downloaded from the EMA website which
contained a MAH representative list ........................................................................................................... 88
Table 32: Demographic data of the participants who took part in the pilot readability test ........................ 88
Table 33: Age range of the participants at the time of the first round of the readability test ...................... 89
Table 34: Education level of the participants involved in the readability test ............................................. 90
Table 35: Number of medicines taken by day by participants at the time of the first round of the
readability test ............................................................................................................................................. 91
213
Table 36: How long participants read a day, and read, heard or saw medical reports in an average week at
the time of the first readability test round ................................................................................................... 91
Table 37: Time in minutes taken by the participants to answer 26 content questions and number of words
contained in each package leaflet ................................................................................................................ 92
Table 38: Calculated median percentage and minimum (min.) and maximum (max.) percentage of correct,
wrong and not found answers itemised for each package leaflet ................................................................ 94
Table 39: Percent correct, wrong and not found answers for each package leaflet for the question ‘Is this
medicine available with or without prescription by a doctor?’ ................................................................... 95
Table 40: Percent correct, wrong and not found answers for each package leaflet for the question ‘Should
you give Enal to other people to use with a similar illness?’ ...................................................................... 96
Table 41: Percent correct, wrong and not found answers for each package leaflet for the question ‘What is
Enal used to treat?’ ...................................................................................................................................... 97
Table 42: Percent correct, wrong and not found answers for each package leaflet for the question ‘Should
women who think they might be pregnant use this medicine?’................................................................... 98
Table 43: Percent correct, wrong and not found answers for each package leaflet for the question ‘Under
what circumstances may breast-feeding women take Enal?’ ...................................................................... 99
Table 44: Percent correct, wrong and not found answers for each package leaflet for the question ‘Can you
take this medicine if you are allergic to lactose?’ ..................................................................................... 100
Table 45: Percent correct, wrong and not found answers for each package leaflet for the question ‘Write
down one reason why your ability to drive may be reduced due to taking Enal.’ ..................................... 101
Table 46: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do if you need a dental operation while taking Enal?’ ............................................................ 102
Table 47: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do if you have just had a kidney transplant and you need Enal?’ ........................................... 104
Table 48: Percent correct, wrong and not found answers for each package leaflet for the question ‘Name
one medicine that is used to treat heart rhythm disorders which can influence Enal.’ .............................. 105
Table 49: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do if you already take medicines to reduce blood sugar levels and also need Enal?’ ............. 106
Table 50: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do with regard to drinking alcohol when taking this medicine?’ ............................................ 107
Table 51: Percent correct, wrong and not found answers for each package leaflet for the question ‘What is
Enal used for treating in children?’ ........................................................................................................... 107
Table 52: Percent correct, wrong and not found answers for each package leaflet for the question ‘What is
the starting dose of Enal to treat high blood pressure in adults?’ .............................................................. 109
214
Table 53: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do if you forget to take a dose of this medicine?’ ................................................................... 109
Table 54: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do if you have taken too much Enal?’ .................................................................................... 110
Table 55: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do if you want to stop taking this medicine?’ ......................................................................... 111
Table 56: Percent correct, wrong and not found answers for each package leaflet for the question ‘How
long should Enal be used?’ ........................................................................................................................ 112
Table 57: Percent correct, wrong and not found answers for each package leaflet for the question ‘How
frequent is the side effect ‘hair loss’?’ ...................................................................................................... 113
Table 58: Percent correct, wrong and not found answers for each package leaflet for the question ‘How
many people are affected by a side effect if it is ‘rare’?’ .......................................................................... 114
Table 59: Answers to the question: ‘How many people are affected by a side effect if it is rare?’ .......... 115
Table 60: Percent correct, wrong and not found answers for each package leaflet for the question ‘In
which of the side effect frequency groups does the following frequency: ‘affects 5 in 100 people’ belong?’
................................................................................................................................................................... 116
Table 61: Percent correct, wrong and not found answers for each package leaflet for the question ‘What
should you do if you notice the side effect runny nose?’ .......................................................................... 117
Table 62: Percent correct, wrong and not found answers for each package leaflet for the question ‘Name
one side effect which requires that you immediately contact a doctor.’ ................................................... 118
Table 63: Percent correct, wrong and not found answers for each package leaflet for the question ‘How
should Enal be stored in relation to children?’ .......................................................................................... 120
Table 64: Percent correct, wrong and not found answers for each package leaflet for the question ‘Name
the active substance in Enal’. .................................................................................................................... 121
Table 65: Percent correct, wrong and not found answers for each package leaflet for the question ‘Can this
tablet be divided?’ ..................................................................................................................................... 122
Table 66: Participants opinions on the structure of the package leaflet .................................................... 123
Table 67: Participants opinions on the comprehensibility of the package leaflet ..................................... 125
Table 68: Participants’ opinion on the information contained in the package leaflet ............................... 127
Table 69: Participants opinion on the readability and motivation to read the package leaflet .................. 128
Table 70: Participants’ opinions on confidence in the package leaflet and the medicine ......................... 130
Table 71: What the participants liked most about each leaflet noted in the free-text field at the end of the
questionnaire ............................................................................................................................................. 132
215
Table 72: What the participants disliked about the package leaflet noted in the free-text field at the end of
the questionnaire ........................................................................................................................................ 134
Table 73: What the participants thought should be deleted in each package leaflet noted in the free-text
field at the end of the questionnaire .......................................................................................................... 136
Table 74: What the participants thought should be included in the package leaflet noted in the free-text
field at the end of the questionnaire .......................................................................................................... 141
Table 75: Number of correct, wrong and not found answers and time needed to provide information for 26
questions relating to content itemised according to age group and package leaflet group summarised for
the three readability test rounds ................................................................................................................. 143
Table 76: Number of correct, wrong and not found answers and time needed to answer 26 questions
relating to the content of the package leaflet itemised according to the number of medicines used per day,
summarised for the three readability test rounds ....................................................................................... 144
Table 77: Number of correct, wrong and not found answers and length of time needed to answer 26
questions on content of the package leaflet according to education level ........................................... 145
Table 78: Significant differences found in the readability test between QRD template 7.3.1 and QRD
template 8 .................................................................................................................................................. 177
Table 79: Significant differences found in the readability test between the model template and QRD
template 8 .................................................................................................................................................. 184
216
List of appendices
Appendix 1: BfArM sample text enalapril………………………………………………………......218
Appendix 2: German BfArM text package leaflet with model template……………………………234
Appendix 3: German BfArM text package leaflet with QRD template 7.3.1……………………….236
Appendix 4: German BfArM text package leaflet with QRD template 8 238
Appendix 5: German short text package leaflet with model template 240
Appendix 6: German short text package leaflet with QRD template 7.3.1 242
Appendix 7: German short text package leaflet with QRD template 8 244
Appendix 8: English short text package leaflet with model template 246
Appendix 9: English short text package leaflet with QRD template 7.3.1 248
Appendix 10: English short text package leaflet with QRD template 8 250
Appendix 11: Questionnaire in English with possible correct answers used in the third round of the
readability test 252
Appendix 12: Questionnaire in German used in the third round of the readability test 256
Appendix 13: Results of the Wilcoxon test to identify significant differences between package leaflet
versions for number of correct answers, wrong answers and not found answers for the 26 content
questions of the readability test 260
Appendix 14: Results of the McNemar test to identify significant differences in the number of correct
answers between short versions of the package leaflets in England 261
Appendix 15: Results of the McNemar test to identify significant differences in the number of correct
answers between short versions of the package leaflets in Germany 262
Appendix 16: Results of the McNemar test to identify significant differences in the number of correct
answers between long versions of the package leaflets in Germany 263
Appendix 17: Results of the McNemar test to identify significant differences in the number of wrong
answers between short versions of the package leaflets in England 264
Appendix 18: Results of the McNemar test to identify significant differences in the number of wrong
answers between short versions of the package leaflets in Germany 265
Appendix 19: Results of the McNemar test to identify significant differences in the number of wrong
answers between long versions of the package leaflets in Germany 266
Appendix 20: Results of the McNemar test to identify significant differences in the number of not found
answers between short versions of the package leaflets in England 267
Appendix 21: Results of the McNemar test to identify significant differences in the number of not found
answers between short versions of the package leaflets in Germany 268
Appendix 22: Results of the McNemar test to identify significant differences in the number of not found
answers between long versions of the package leaflets in Germany 269
217
Appendix 23: Results of the McNemar test to identify significant differences in the number of not found
answers between long versions of the package leaflets in Germany 270
Appendix 24: Results of the Pearson’s chi-square test to identify significant differences in the time taken
to answer the 26 content questions according to age group for the long versions of the package leaflet in
Germany 271
Appendix 25: Results of the Pearson’s chi-square test to identify significant differences in the time taken
to answer the 26 content questions according to number of medicines taken per day for the long versions
of the package leaflet in Germany 272
218
Appendices
Appendix 1: BfArM sample text enalapril
Muster-Nr. 8000142 Stand: 07.04.2009 Dateiname: palde-enalapril-oral-2009-04-09-005
Enalaprilmaleat Tablette 2,5 mg / 5 mg / 10 mg / 20 mg
M2 Stoff Darreichungsform Stärke
PA Anlage
PB Wortlaut der für die Packungsbeilage vorgesehenen Angaben
PCX Gebrauchsinformation
Lesen Sie die gesamte Packungsbeilage / Gebrauchsinformation sorgfältig durch, bevor Sie mit der Einnahme dieses Arzneimittels beginnen. - Heben Sie die Packungsbeilage auf. Vielleicht möchten Sie diese später
nochmals lesen. - Wenn Sie weitere Fragen haben, wenden Sie sich bitte an Ihren Arzt oder
Apotheker. - Dieses Arzneimittel wurde Ihnen persönlich verschrieben und darf nicht an
Dritte weiter gegeben werden. Es kann anderen Menschen schaden, auch wenn diese dasselbe Krankheitsbild haben wie Sie.
1. Was ist /.../ und wofür wird es angewendet?2. Was müssen Sie vor der Einnahme von /.../ beachten?3. Wie ist /.../ einzunehmen?4. Welche Nebenwirkungen sind möglich?5. Wie ist /.../ aufzubewahren?6. Weitere Angaben
[(Handels)Name Stärke Darreichungsform]
PF Wirkstoff: Enalaprilmaleat
PG Der arzneilich wirksame Bestandteil ist Enalaprilmaleat.
/Für Tabletten 2,5 mg / 5 mg / 10 mg / 20 mg: 1 Tablette enthält 2,5 mg / 5 mg / 10 mg / 20 mg Enalaprilmaleat./
PH Die sonstigen Bestandteile sind: [Angaben entsprechend der Zusammensetzung]
P4 [Darreichungsform und Inhalt / für den Patienten erhältliche Packungsgrößen] /.../ ist in Packungen mit ... Tabletten erhältlich.
PC1 1. WAS IST /.../ UND WOFÜR WIRD ES ANGEWENDET?
219
PI 1.1 /.../ ist ein ACE-Hemmer, d.h. ein Arzneimittel mit blutdrucksenkenden und
herzentlastenden Eigenschaften.
PD 1.2 von: [Name, Anschrift des pharmazeutischen Unternehmers, optional Telefon- und Telefaxnummer, E-Mail-Adresse und Internet-Adresse]
P5 hergestellt von: [Name, Anschrift des Herstellers, optional Telefon- und Telefaxnummer, E-Mail-Adresse und Internet-Adresse; kann entfallen, wenn mit pharmazeutischem Unternehmer identisch]
PK /.../ wird angewendet
zur Behandlung eines hohen Blutdrucks (Hypertonie)
zur Behandlung einer Herzleistungsschwäche (symptomatische Herzinsuffizienz)
zur Vorbeugung der Entwicklung einer Herzleistungsschwäche (symptomatische Herzinsuffizienz) bei Patienten mit einer Funktionseinschränkung der linken Herzkammer, die noch keine Zeichen einer Herzleistungsschwäche verursacht (asymptomatische linksventrikuläre Dysfunktion mit einer linksventrikulären Aus-wurffraktion [LVEF] ≤ 35%).
PC2 2. WAS MÜSSEN SIE VOR DER EINNAHME VON /.../ BEACHTEN?
PL 2.1 /.../ darf nicht eingenommen werden:
- wenn sie überempfindlich (allergisch) gegenüber dem Wirkstoff Enalaprilmaleat, einen
anderen ACE-Hemmer oder einen der sonstigen Bestandteile von /.../ sind
- wenn bei Ihnen während einer früheren Behandlung mit einem ACE-Hemmer Gewebeschwellungen (angioneurotische Ödeme) auftraten
- wenn Sie eine vererbte Neigung zu Gewebeschwellungen oder Gewebeschwellungen aus unbekannter Ursache haben (hereditäres oder idiopathisches Angioödem)
- während der letzten 6 Schwangerschaftsmonate. (Es wird empfohlen, [Arzneimittel] auch in der frühen Phase der Schwangerschaft nicht anzuwenden, siehe Abschnitt Schwangerschaft und Stillzeit).’
PV 2.2 Besondere Vorsicht bei der Einnahme von /.../ ist erforderlich
- Wenn Sie an folgenden Erkrankungen leiden bzw. folgende Umstände bei Ihnen
vorliegen, informieren Sie bitte Ihren Arzt bevor Sie das Arzneimittel einnehmen. Dieser
wird die nötigen Vorsichtsmaßnahmen treffen.
- wenn bei Ihnen das Risiko eines übermäßigen Blutdruckabfalls besteht, weil Sie an Störungen des Salz- und Flüssigkeitshaushaltes leiden, z.B. weil Sie harntreibende Arzneimittel einnehmen oder eine salzarme Diät durchführen oder als Folge von Erbrechen oder Durchfall
- wenn die Herzklappen Ihrer linken Herzkammer verengt sind oder andere Ausflussbehinderungen aus der linken Herzkammer bestehen
- wenn Sie an einer Herzerkrankung mit Unterbrechung der Durchblutung (Ischämie) leiden
220
- wenn Sie an Durchblutungsstörungen des Gehirns (zerebrovaskuläre Erkrankung) leiden
- wenn Ihre Nierenfunktion eingeschränkt ist (Kreatinin-Clearance unter 80 ml/Minute)
- wenn bei Ihnen eine Einengung der Nierenschlagadern vorliegt (beidseitig bzw. einseitig bei Einzelniere)
- wenn bei Ihnen kürzlich eine Nierenverpflanzung durchgeführt wurde
- wenn bei Ihnen die Leberenzymwerte ansteigen oder Sie eine Gelbsucht entwickeln
- wenn bei Ihnen die Anzahl der weißen Blutkörperchen abnimmt (Leukopenie) bzw. sich eine hochgradige Verminderung bestimmter weißer Blutkörperchen mit Infektneigung und schweren Allgemeinsymptomen (Agranulozytose) entwickelt
- wenn Sie an einer bestimmten Erkrankung des Bindegewebes (Kollagenosen) mit Gefäßbeteiligung leiden
- wenn Sie mit Arzneimitteln behandelt werden, die Ihre Abwehrreaktionen unterdrücken
- wenn Sie gleichzeitig Allopurinol (Arzneimittel gegen Gicht), Procainamid (Arzneimittel gegen Herzrhythmusstörungen) oder Lithium (Arzneimittel gegen bestimmte Depressionen) einnehmen
- wenn bei Ihnen während der Behandlung mit /.../ Überempfindlichkeitsreaktionen bzw. Gewebeschwellungen (Angio ödeme) auftreten
- wenn Sie unter Zuckerkrankheit leiden (Diabetes mellitus)
- wenn bei Ihnen ein hartnäckiger trockner Husten auftritt
- wenn bei Ihnen das Risiko einer Erhöhung der Kaliumwerte im Blut besteht
- wenn die Blutdrucksenkung aufgrund Ihrer ethnischen Zugehörigkeit (insbesondere bei Patienten mit schwarzer Hautfarbe) nicht ausreichend stark ist.
Wenn bei Ihnen eine Desensibilisierungstherapie gegen Insektengifte (z.B. von Bienen oder
Wespen) notwendig ist, ist /.../ vorübergehend durch ein geeignetes Arzneimittel aus einer
anderen Stoffklasse zu ersetzen. Es können sonst lebensbedrohliche
Überempfindlichkeitsreaktionen (z.B. Blutdruckabfall, Atemnot, Erbrechen, allergische Haut-
reaktionen) auftreten. Solche Reaktionen können auch nach Insektenstichen (von z.B. Bienen
oder Wespen) vorkommen.
Die gleichzeitige Anwendung von /.../ bei einer Blutwäsche (Dialyse) mit bestimmten
Dialysemembranen (High-flux-Membranen) bzw. bei einer Behandlung von stark erhöhten Blut-
fetten (LDL-Apherese mit Dextransulfat-Absorption) können schwere Überempfindlichkeits-
reaktionen bis hin zum lebensbedrohlichen Schock auslösen.
Im Falle einer notfallmäßigen Blutwäsche oder Hämofiltration oder der Notwendigkeit einer LDL-
Apherese muss deshalb vorher auf ein anderes für das betreffende Anwendungsgebiet
geeignetes Arzneimittel – keinen ACE-Hemmer – umgestellt werden oder eine andere
Dialysemembran verwendet werden.
Teilen Sie Ihrem Arzt mit, dass Sie mit /.../ behandelt werden bzw. Dialysen benötigen, damit der
Arzt dies bei der Behandlung berücksichtigen kann.
221
Falls Sie vor einer Operation oder Narkose (auch beim Zahnarzt) stehen, teilen Sie Ihrem Arzt
mit, dass Sie /.../ einnehmen, da es unter der Narkose zu einem plötzlichen Blutdruckabfall
kommen kann.
Informieren Sie sofort Ihren Arzt, falls bei Ihnen folgende Krankheitszeichen auftreten:
- Schwellung von Gesicht, Gliedmaßen, Lippen, Schleimhaut, Zunge und/oder Kehlkopf, Atemnot
- Gelbfärbung von Haut und Schleimhäuten
- Fieber, Lymphknotenschwellung und/oder Halsentzündung.
- In diesen Fällen dürfen Sie /.../ nicht weiter einnehmen und Ihr Arzt wird entsprechende
Maßnahmen ergreifen.
Die Anwendung dieses Arzneimittels bedarf der regelmäßigen ärztlichen Kontrolle. Halten Sie
daher bitte die vom Arzt angeordneten Laborkontrollen und Untersuchungen unbedingt ein.
Kinder
Die Daten zur Anwendung von Enalaprilmaleat bei Kindern mit Bluthochdruck sind begrenzt. Bezüglich der anderen Anwendungsgebiete gibt es keine Daten. Zur Anwendung von Enalprilmaleat liegen Daten zur Verträglichkeit und Wirksamkeit nur zu Anwendung von Enalaprilmaleat bei Kindern ab 6 Jahren in der Behandlung von Bluthochdruck vor, daher wird /.../ für Kinder ausschließlich zur Behandlung dieser Erkrankung empfohlen.
Neugeborene und Kinder mit Nierenerkrankungen sollen nicht mit /.../ behandelt werden.
PV3 Schwangerschaft
Teilen Sie Ihrem Arzt mit, wenn Sie vermuten, schwanger zu sein oder schwanger werden könnten. In der Regel wird Ihr Arzt Ihnen empfehlen, [Arzneimittel] vor einer Schwangerschaft bzw. sobald Sie wissen, dass Sie schwanger sind, abzusetzen, und er wird Ihnen ein anderes Arzneimittel empfehlen. Die Anwendung von [Arzneimittel] in der frühen Schwangerschaft wird nicht empfohlen und [Arzneimittel] darf nicht mehr nach dem dritten Schwangerschaftsmonat eingenommen werden, da die Einnahme von [Arzneimittel] in diesem Stadium zu schweren Schädigungen Ihres ungeborenen Kindes führen kann.
PV4 Stillzeit
Teilen sie Ihrem Arzt mit, wenn Sie stillen oder mit dem Stillen beginnen wollen. Das Stillen von Neugeborenen (in den ersten Wochen nach der Geburt) und besonders von Frühgeburten wird nicht empfohlen, wenn Sie [Arzneimittel] einnehmen. Bei älteren Säuglingen sollte der Arzt Sie über Nutzen und mögliche Schäden der Anwendung von [Arzneimittel] in der Stillzeit im Vergleich zu Behandlungsalternativen aufklären.
PV5 Verkehrstüchtigkeit und das Bedienen von Maschinen
Die Behandlung mit diesem Arzneimittel bedarf der regelmäßigen ärztlichen Kontrolle. Durch individuell auftretende unterschiedliche Reaktionen kann das Reaktionsvermögen so weit
222
verändert sein, dass die Fähigkeit zur aktiven Teilnahme am Straßenverkehr, zum Bedienen von Maschinen oder zum Arbeiten ohne sicheren Halt beeinträchtigt wird. Dies gilt in verstärktem Maße bei Behandlungsbeginn, Dosiserhöhung und Präparatewechsel sowie im Zusammenwirken mit Alkohol.
PN 2.3 Wechselwirkungen mit anderen Arzneimitteln
Bitte informieren Sie Ihren Arzt oder Apotheker, wenn Sie andere Arzneimittel einnehmen bzw.
vor kurzem eingenommen haben, auch wenn es sich um nicht verschreibungspflichtige
Arzneimittel handelt.
Bei gleichzeitiger Einnahme von /.../ und anderen Arzneimitteln ist insbesondere zu berücksichtigen:
- Harntreibende Arzneimittel mit verminderter Kaliumausscheidung (kaliumsparende Diuretika) und Kaliumpräparate: ACE-Hemmer mildern den Kaliumverlust durch harntreibende Arzneimittel. Bestimmte harntreibende Arzneimittel (kaliumsparende Diuretika, wie z. B. Spironolacton, Triamteren oder Amilorid), Kaliumpräparate, kaliumhaltige Salzersatzmittel oder Heparin (gerinnungshemmendes Arzneimittel) können zu einem deutlichen Anstieg des Kaliumwertes im Blut führen. Die gleichzeitige Anwendung sollte mit Vorsicht und unter häufiger Überprüfung der Kaliumwerte im Blut erfolgen.
- Andere harntreibende Arzneimittel (Thiazide oder Schleifendiuretika):
Eine vorangegangene hoch dosierte Behandlung mit harntreibenden Arzneimitteln kann zu
Volumenmangel und damit zum Risiko eines Blutdruckabfalls bei Therapiebeginn mit /.../
führen. Die blutdrucksenkende Wirkung kann durch Absetzen des harntreibenden
Arzneimittels, einem Ausgleich des Volumenmangels bzw. Gabe von Salz oder durch
Einleitung der Therapie mit Enalaprilmaleat in niedriger Dosierung vermindert werden.
- Andere blutdrucksenkende Arzneimittel (Antihypertensiva): Die gleichzeitige Anwendung von /.../ mit anderen blutdrucksenkenden Arzneimitteln kann die blutdrucksenkende Wirkung von /.../ verstärken. Auch die gleichzeitige Anwendung von Nitroglyzerin und anderen Nitraten oder anderen gefäßerweiternd wirkenden Arzneimitteln (Vasodilatatoren) kann den Blutdruck weiter senken.
- Lithium (Arzneimittel gegen Depressionen): Unter der gleichzeitigen Anwendung von ACE-Hemmern und Lithium wurde über reversible Anstiege der Lithiumwerte im Blut und schädliche (toxische) Effekte berichtet. Eine gleichzeitige Therapie mit bestimmten harntreibenden Arzneimitteln (Thiaziddiuretika) kann die Lithium-Konzentration im Blut und damit das Risiko einer schädlichen Wirkung von Lithium unter einer ACE-Hemmer-Therapie erhöhen. Die Anwendung von /.../ mit Lithium wird deshalb nicht empfohlen; sollte diese Kombination aber erforderlich sein, sind die Lithiumwerte im Blut sorgfältig zu überwachen.
- Arzneimittel gegen Depressionen sowie gegen andere psychische Erkrankungen, Betäubungsmittel, Narkosemittel (trizyklische Antidepressiva, Neuroleptika, Anästhetika, Narkotika): Eine gleichzeitige Anwendung mit ACE-Hemmern kann zu einer verstärkten Blutdrucksenkung führen.
- Arzneimittel gegen Schmerzen und Entzündungen (nicht steroidale Antiphlogistika):
Die Dauertherapie mit Arzneimitteln gegen Schmerzen und Entzündungen kann die
blutdrucksenkende Wirkung von ACE-Hemmern abschwächen. Eine gleichzeitige
223
Behandlung kann zu einer Erhöhung der Kaliumwerte im Blut und zu einer
Verschlechterung der Nierenfunktion führen, die gewöhnlich reversibel ist. Selten kann es
auch zu akutem Nierenversagen kommen, insbesondere bei Patienten mit eingeschränkter
Nierenfunktion z.B. bei älteren Patienten oder Patienten mit Flüssigkeitsmangel.
- Sympathomimetika (Mittel, die ähnliche Wirkungen wie die körpereigenen Überträgerstoffe Noradrenalin bzw. Adrenalin hervorrufen, z. B. Blutdrucksteigerung): Sympathomimetika können die blutdrucksenkende Wirkung von ACE-Hemmern abschwächen.
- Blutzuckersenkende Arzneimittel und Insulin (Antidiabetika): Bei gleichzeitiger Anwendung mit ACE-Hemmern kann es zu einer Verstärkung der blutzuckersenkenden Wirkung kommen; es besteht das Risiko, dass Blutzuckerwerte unter Normalwerte absinken (Hypoglykämie). Diese Fälle treten offenbar insbesondere in den ersten Wochen der kombinierten Behandlung sowie bei Patienten mit eingeschränkter Nierenfunktion auf.
- Acetylsalicylsäure (Arzneimittel, das in niedriger Dosierung zum Schutz vor Herz-Kreislauf-Erkrankungen eingesetzt wird), Arzneimittel zur Auflösung von Blutgerinnseln (Thrombolytika), Betablocker (Arzneimittel z.B. zur Behandlung des Bluthochdrucks): Eine gleichzeitige Behandlung mit /.../ kann erfolgen.
2.4 Bei Einnahme von /.../ zusammen mit Nahrungsmitteln und Getränken:
Die Nahrungsaufnahme hat keinen Einfluss auf die Aufnahme von /.../ in den Körper.
Alkohol verstärkt die blutdrucksenkende Wirkung von ACE-Hemmern. PC3 3. Wie ist /.../ einzunehmen? PMX Nehmen Sie /.../ immer genau nach der Anweisung des Arztes ein. Bitte fragen Sie bei Ihrem Arzt oder Apotheker nach, wenn Sie sich nicht ganz sicher sind. Es ist sehr wichtig, dass Sie /.../ einnehmen, solange es Ihnen Ihr Arzt verordnet.
3.1 Art der Anwendung
Tabletten zum Einnehmen.
3.2 Ihr Arzt wird Ihre anfängliche Dosis individuell nach Ihrem Gesundheitszustand und dem Schweregrad Ihrer Erkrankung wählen und entsprechend der Wirkung des Arzneimittels auf Ihren Blutdruck die Dosis schrittweise anpassen. Falls vom Arzt nicht anders verordnet, ist die übliche
Dosis:
/Für Tabletten 2,5 mg:
Bluthochdruck
Anfangsdosis:
224
Die Anfangsdosis beträgt 1-mal täglich 2 Tabletten /.../ (entsprechend 5 mg Enalaprilmaleat) bis maximal 20 mg Enalaprilmaleat je nach Schweregrad der Erkrankung und Ihrem Zustand.
- Leichter Bluthochdruck: Die empfohlene Anfangsdosis beträgt 1-mal täglich 2 Tabletten /.../ (entsprechend 5 mg Enalaprilmaleat) bis zu 10 mg Enalaprilmaleat täglich.
Patienten mit stark aktiviertem blutdruckregulierendem System z. B. bei Bluthochdruck aufgrund einer Nierenerkrankung, Salz- und/oder Flüssigkeitsmangel, nicht ausgeglichener Herzleistungsschwäche oder schwerem Bluthochdruck: Die Therapie wird mit 1-mal täglich 2 Tabletten /.../ (entsprechend 5 mg Enalaprilmaleat) oder einer geringeren Dosis eingeleitet. Bei Therapiebeginn kann es zu einem übermäßigen Blutdruckabfall kommen; eine engmaschige ärztliche Überwachung ist erforderlich.
- Patienten mit vorausgegangener Therapie mit hoch dosierten harn-treibenden Arzneimitteln (Diuretika): Die Therapie wird mit 1-mal täglich 2 Tabletten /.../ (entsprechend 5 mg Enalaprilmaleat) oder einer geringeren Dosis eingeleitet. Eine vorausgegangene Therapie mit hoch dosierten harntreibenden Arzneimitteln kann zu einem Flüssigkeitsmangel führen, so dass die Gefahr eines Blutdruckabfalls bei Therapiebeginn besteht. Wenn möglich sollten diese Arzneimittel 2-3 Tage lang abgesetzt werden, bevor die Therapie mit /.../ eingeleitet wird. Die Nierenfunktion und die Kaliumwerte im Blut sollten überwacht werden.
Erhaltungsdosis:
Die übliche Erhaltungsdosis beträgt 20 mg Enalaprilmaleat täglich. Eine Tageshöchstdosis von 40 mg Enalaprilmaleat sollte nicht überschritten werden.
Für die höheren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung.
Herzleistungsschwäche (symptomatische Herzinsuffizienz)/ Funktionsstörung der linken Herzkammer (asymptomatische linksventrikuläre Dysfunktion)
Anfangsdosis:
/.../ wird bei der Behandlung der Herzleistungsschwäche üblicherweise zusätzlich zu harntreibenden Arzneimitteln und Digitalis oder Betablockern angewendet.
Die Anfangsdosis beträgt 1-mal täglich 1 Tablette /.../ (entsprechend 2,5 mg Enalaprilmaleat).
Die Therapie ist unter engmaschiger ärztlicher Überwachung einzuleiten, um die anfängliche Wirkung auf den Blutdruck zu ermitteln.
Erhaltungsdosis:
Zu Beginn der Therapie mit /.../ kann es bei Patienten mit Herzleistungsschwäche zu einem Blutdruckabfall kommen. Wenn dieser behoben ist, sollte die Dosis schrittweise über einen Zeitraum von 2-4 Wochen auf die Erhaltungsdosis von 20 mg Enalaprilmaleat täglich gesteigert werden. Diese Dosis kann als Ein zeldosis eingenommen oder auf zwei Gaben verteilt werden, je nach Verträglichkeit.
Eine Tageshöchstdosis von 40 mg Enalaprilmaleat, auf 2 Gaben verteilt, sollte nicht überschritten werden.
Für die höheren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung./
225
/Für Tabletten 5 mg:
Bluthochdruck
Anfangsdosis:
Die Anfangsdosis beträgt 1-mal täglich 1 Tablette /.../ (entsprechend 5 mg Enalaprilmaleat) bis maximal 20 mg Enalaprilmaleat je nach Schweregrad der Erkrankung und Ihrem Zustand.
- Leichter Bluthochdruck: Die empfohlene Anfangsdosis beträgt 1-mal täglich 1 Tablette /.../ (entsprechend 5 mg Enalaprilmaleat) bis 1-mal täglich 2 Tabletten /.../ (entsprechend 10 mg Enalaprilmaleat).
Patienten mit stark aktiviertem blutdruckregulierendem System z. B. bei Bluthochdruck
aufgrund einer Nierenerkrankung, Salz- und/oder Flüssigkeitsmangel, nicht ausgeglichener
Herzleistungsschwäche oder schwerem Bluthochdruck:
Die Therapie wird mit 1-mal täglich 1 Tablette /.../ (entsprechend 5 mg Enalaprilmaleat)
oder einer geringeren Dosis eingeleitet. Bei Therapiebeginn kann es zu einem
übermäßigen Blutdruckabfall kommen; eine engmaschige ärztliche Überwachung ist
erforderlich.
Patienten mit vorausgegangener Therapie mit hoch dosierten harntreibenden Arzneimitteln
(Diuretika):
Die Therapie wird mit 1-mal täglich 1 Tablette /.../ (entsprechend 5 mg Enalaprilmaleat)
oder einer geringeren Dosis eingeleitet.
Eine vorausgegangene Therapie mit hoch dosierten harntreibenden Arzneimitteln kann zu
einem Flüssigkeitsmangel führen, so dass die Gefahr eines Blutdruckabfalls bei
Therapiebeginn besteht. Wenn möglich sollten diese Arzneimittel 2-3 Tage lang abgesetzt
werden, bevor die Therapie mit /.../ eingeleitet wird. Die Nierenfunktion und die Kaliumwerte im
Blut sollten überwacht werden.
Erhaltungsdosis:
Die übliche Erhaltungsdosis beträgt 20 mg Enalaprilmaleat täglich. Eine Tageshöchstdosis von 40 mg Enalaprilmaleat sollte nicht überschritten werden.
Für die höheren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung.
Herzleistungsschwäche (symptomatische Herzinsuffizienz)/ Funktionsstörung der linken Herzkammer (asymptomatische linksventrikuläre Dysfunktion)
Anfangsdosis:
/.../ wird bei der Behandlung der Herzleistungsschwäche üblicherweise zusätzlich zu harntreibenden Arzneimitteln und Digitalis oder Betablockern angewendet.
Die Anfangsdosis beträgt 1-mal täglich 2,5 mg Enalaprilmaleat.
Die Therapie ist unter engmaschiger ärztlicher Überwachung einzuleiten, um die anfängliche Wirkung auf den Blutdruck zu ermitteln.
Erhaltungsdosis:
Zu Beginn der Therapie mit /.../ kann es bei Patienten mit Herzleistungsschwäche zu einem Blutdruckabfall kommen. Wenn dieser behoben ist, sollte die Dosis schrittweise über einen
226
Zeitraum von 2-4 Wochen auf die Erhaltungsdosis von 20 mg Enalaprilmaleat täglich ge-steigert werden. Diese Dosis kann als Einzeldosis eingenommen oder auf zwei Gaben verteilt werden, je nach Verträglichkeit.
Eine Tageshöchstdosis von 40 mg Enalaprilmaleat, auf 2 Gaben verteilt, sollte nicht überschritten werden.
Für die höheren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung./
/Für Tabletten 10 mg:
Bluthochdruck
Anfangsdosis:
Die Anfangsdosis beträgt 1-mal täglich 5 mg Enalaprilmaleat bis maximal 20 mg Enalaprilmaleat je nach Schweregrad der Erkrankung und Ihrem Zustand.
- Leichter Bluthochdruck: Die empfohlene Anfangsdosis beträgt 1-mal täglich 5 mg Enalaprilmaleat bis zu 1-mal täglich 1 Tablette /.../ (entsprechend 10 mg Enalaprilmaleat) täglich.
- Patienten mit stark aktiviertem blutdruckregulierendem System z. B. bei Bluthochdruck aufgrund einer Nierenerkrankung, Salz- und/oder Flüssigkeitsmangel, nicht ausgeglichener Herzleistungsschwäche oder schwerem Bluthochdruck: Die Therapie wird mit 1-mal täglich 5 mg Enalaprilmaleat oder einer geringeren Dosis eingeleitet. Bei Therapiebeginn kann es zu einem übermäßigen Blutdruckabfall kommen; eine engmaschige ärztliche Überwachung ist erforderlich.
- Patienten mit vorausgegangener Therapie mit hoch dosierten harn-treibenden Arzneimitteln (Diuretika): Die Therapie wird mit 1-mal täglich 5 mg Enalaprilmaleat oder einer geringeren Dosis eingeleitet. Eine vorausgegangene Therapie mit hoch dosierten harntreibenden Arzneimitteln kann zu einem Flüssigkeitsmangel führen, so dass die Gefahr eines Blutdruckabfalls bei Therapiebeginn besteht. Wenn möglich sollten diese Arzneimittel 2-3 Tage lang abgesetzt werden, bevor die Therapie mit /.../ eingeleitet wird. Die Nierenfunktion und die Kaliumwerte im Blut sollten überwacht werden.
Erhaltungsdosis:
Die übliche Erhaltungsdosis beträgt 2 Tabletten /.../ (entsprechend 20 mg Enalaprilmaleat) täglich. Eine Tageshöchstdosis von 40 mg Enalaprilmaleat sollte nicht überschritten werden.
Für die niedrigeren und höheren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung.
Herzleistungsschwäche (symptomatische Herzinsuffizienz)/ Funktionsstörung der linken
Herzkammer (asymptomatische linksventrikuläre Dysfunktion)
Anfangsdosis:
/.../ wird bei der Behandlung der Herzleistungsschwäche üblicherweise zusätzlich zu harntreibenden Arzneimitteln und Digitalis oder Betablockern angewendet.
Die Anfangsdosis beträgt 1-mal täglich 2,5 mg Enalaprilmaleat.
227
Die Therapie ist unter engmaschiger ärztlicher Überwachung einzuleiten, um die anfängliche Wirkung auf den Blutdruck zu ermitteln.
Erhaltungsdosis:
Zu Beginn der Therapie mit /.../ kann es bei Patienten mit Herzleistungsschwäche zu einem Blutdruckabfall kommen. Wenn dieser behoben ist, sollte die Dosis schrittweise über einen Zeitraum von 2-4 Wochen auf die Erhaltungsdosis von 2 Tabletten /.../ (entsprechend 20 mg Enalaprilmaleat) täglich gesteigert werden. Diese Dosis kann als Einzeldosis eingenommen oder auf zwei Gaben verteilt werden, je nach Verträglichkeit.
Eine Tageshöchstdosis von 40 mg Enalaprilmaleat, auf 2 Gaben verteilt, sollte nicht
überschritten werden.
Für die niedrigeren und höheren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung./
/Für Tabletten 20 mg:
Bluthochdruck
Anfangsdosis:
Die Anfangsdosis beträgt 1-mal täglich 5 mg Enalaprilmaleat bis maximal 1-mal täglich 1 Tablette /.../ (entsprechend 20 mg Enalaprilmaleat) je nach Schweregrad der Erkrankung und Ihrem Zustand.
- Leichter Bluthochdruck: Die empfohlene Anfangsdosis beträgt 1-mal täglich 5 mg Enalaprilmaleat bis zu 10 mg Enalaprilmaleat täglich.
- Patienten mit stark aktiviertem blutdruckregulierendem System z. B. bei Bluthochdruck aufgrund einer Nierenerkrankung, Salz- und/oder Flüssigkeitsmangel, nicht ausgeglichener Herzleistungsschwäche oder schwerem Bluthochdruck: Die Therapie wird mit 1-mal täglich 5 mg Enalaprilmaleat oder einer geringeren Dosis eingeleitet. Bei Therapiebeginn kann es zu einem übermäßigen Blutdruckabfall kommen; eine engmaschige ärztliche Überwachung ist erforderlich.
- Patienten mit vorausgegangener Therapie mit hoch dosierten harn-treibenden Arzneimitteln (Diuretika): Die Therapie wird mit 1-mal täglich 5 mg Enalaprilmaleat oder einer geringeren Dosis eingeleitet. Eine vorausgegangene Therapie mit hoch dosierten harntreibenden Arzneimitteln kann zu einem Flüssigkeitsmangel führen, so dass die Gefahr eines Blutdruckabfalls bei Therapiebeginn besteht. Wenn möglich sollten diese Arzneimittel 2-3 Tage lang abgesetzt werden, bevor die Therapie mit /.../ eingeleitet wird. Die Nierenfunktion und die Kaliumwerte im Blut sollten überwacht werden.
Erhaltungsdosis:
Die übliche Erhaltungsdosis beträgt 1-mal täglich 1 Tablette /.../ (entsprechend 20 mg Enalaprilmaleat). Eine Tageshöchstdosis von 40 mg Enalaprilmaleat sollte nicht überschritten werden.
Für die niedrigeren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung.
228
Herzleistungsschwäche (symptomatische Herzinsuffizienz)/ Funktionsstörung der linken Herzkammer (asymptomatische linksventrikuläre Dysfunktion)
Anfangsdosis:
/.../ wird bei der Behandlung der Herzleistungsschwäche üblicherweise zusätzlich zu harntreibenden Arzneimitteln und Digitalis oder Betablockern angewendet.
Die Anfangsdosis beträgt 1-mal täglich 2,5 mg Enalaprilmaleat.
Die Therapie ist unter engmaschiger ärztlicher Überwachung einzuleiten, um die anfängliche Wirkung auf den Blutdruck zu ermitteln.
Erhaltungsdosis:
Zu Beginn der Therapie mit /.../ kann es bei Patienten mit Herzleistungsschwäche zu einem Blutdruckabfall kommen. Wenn dieser behoben ist, sollte die Dosis schrittweise über einen Zeitraum von 2-4 Wochen auf die Erhaltungsdosis von 20 mg Enalaprilmaleat täglich ge-steigert werden. Diese Dosis kann als Einzeldosis eingenommen oder auf zwei Gaben verteilt werden, je nach Verträglichkeit.
Eine Tageshöchstdosis von 2-mal 1 Tablette /.../ (entsprechend 40 mg Enalaprilmaleat), auf 2 Gaben verteilt, sollte nicht überschritten werden.
Für die niedrigeren Dosierungen stehen Tabletten mit geeigneter Wirkstoffstärke zur Verfügung.//
Sie sollten besonders vorsichtig sein, wenn Sie Ihre erste Dosis einnehmen oder wenn Ihre
Dosis erhöht wird. Teilen Sie Ihrem Arzt unverzüglich mit, wenn Sie sich benommen oder
schwindlig fühlen.
Vor und nach Beginn der Einnahme von /.../ sollten Blutdruck und Nierenfunktion engmaschig überwacht werden, da über Blutdruckabfall und (seltener) nachfolgendem Nierenversagen berichtet wurde. Wenn Sie mit harntreibenden Arzneimitteln behandelt werden, sollte – falls möglich – deren Dosis vor Beginn der Einnahme von /.../ verringert werden. Ein Blutdruckabfall bei Therapiebeginn mit /.../ bedeutet nicht, dass auch während der Dauer-behandlung mit /.../ solche Reaktionen auftreten werden und schließt die Weiterbehandlung mit dem Arzneimittel nicht aus. Die Kaliumwerte im Blut und die Nierenfunktion sollten ebenfalls überwacht werden.
Dosierung bei eingeschränkter Nierenfunktion
Grundsätzlich sollten die Abstände zwischen den Anwendungen von /.../ verlängert werden
und/oder die Dosis reduziert werden.
Ihr Arzt wird Ihre Behandlung individuell festlegen.
Bei mäßiger Einschränkung der Nierenfunktion wird eine Dosis von 1-mal täglich 5-10 mg
Enalaprilmaleat empfohlen.
Bei schwerer Nierenfunktionseinschränkung wird eine Dosis von 1-mal täglich 2,5 mg
Enalaprilmaleat empfohlen.
Für Dialysepatienten wird eine Dosis von 1-mal täglich 2,5 mg Enalaprilmaleat an Dialyse-Tagen
empfohlen. An dialysefreien Tagen richtet sich die Dosis nach der Blutdrucksenkung.
229
Dosierung bei älteren Patienten
Die Dosis sollte sich nach der Nierenfunktion des Patienten richten.
Dosierung bei Kindern
Wenn die Kinder Tabletten schlucken können, wird die Dosis vom Arzt individuell dem Zustand des Kindes und der Blutdrucksenkung angepasst.
Die empfohlene Anfangsdosis für Kinder mit Bluthochdruck und mit einem Gewicht von 20 kg bis 50 kg beträgt 1-mal täglich 2,5 mg Enalaprilmaleat; Kinder, die mehr als 50 kg wiegen, erhalten 1-mal täglich 5 mg Enalaprilmaleat. Die weitere Dosierung wird vom Arzt dem Bedarf des Kindes angepasst. Dabei darf eine Tageshöchstdosis von 20 mg Enalaprilmaleat für Kinder mit 20 kg bis 50 kg Körpergewicht bzw. 40 mg Enalaprilmaleat für Kinder mit mehr als 50 kg Körpergewicht nicht überschritten werden.
Neugeborene und Kinder mit Nierenerkrankungen sollen nicht mit /.../ behandelt werden.
Nehmen Sie die Tabletten unzerkaut mit ausreichend Flüssigkeit (z.B. einem Glas Wasser) ein. Die Einnahme kann unabhängig von den Mahlzeiten erfolgen. Die angegebene Tagesmenge wird in der Regel morgens auf einmal eingenommen, kann aber gegebenenfalls auch auf 2 Einnahmen morgens und abends verteilt werden.
Die Dauer der Behandlung bestimmt Ihr Arzt. Die Behandlung mit /.../ ist in der Regel eine
Langzeittherapie.
Bitte sprechen Sie mit Ihrem Arzt, wenn Sie den Eindruck haben, dass die Wirkung von /...zu stark oder zu schwach ist.
3.3 Wenn Sie eine größere Menge /.../ eingenommen haben, als Sie sollten:
Wenn Sie durch ein Versehen zu viele Tabletten eingenommen haben oder ein Kind einige Tabletten geschluckt hat, wenden Sie sich sofort an einen Arzt/Notarzt. Dieser kann entsprechend der Schwere der Vergiftung über die erforderlichen Maßnahmen entscheiden.
In Abhängigkeit vom Ausmaß der Überdosierung sind folgende Symptome möglich: Starker Blutdruckabfall, starker Blutdruckabfall, Kreislaufversagen, beschleunigter oder verlangsamter Herzschlag, Herzklopfen, Nierenversagen, Atembeschleunigung, Schwindel, Angstgefühl und Husten. Bei Verdacht auf eine Überdosierung benötigen Sie ärztliche Hilfe!
3.4 Wenn Sie die Einnahme von /.../ vergessen haben:
Nehmen Sie beim nächsten Mal nicht zusätzlich mehr Tabletten ein, sondern setzen Sie die
Einnahme von /.../ wie verordnet fort.
3.5 Auswirkungen, wenn die Behandlung mit /.../ abgebrochen wird:
Unterbrechen oder beenden Sie die Behandlung mit /.../ nicht ohne Rücksprache mit Ihrem behandelnden Arzt!
Bei Patienten mit Bluthochdruck kann der Blutdruck erneut ansteigen und bei Patienten mit Herzleistungsschwäche können die Symptome wieder auftreten.
230
PC4 4. WELCHE NEBENWIRKUNGEN SIND MÖGLICH?
PM Wie alle Arzneimittel kann /.../ Nebenwirkungen haben. Diese treten jedoch nicht bei
jedem Patienten auf. Unerwünschte Wirkungen, die von /.../ oder anderen ACE-Hemmern
bekannt sind, finden Sie nachfolgend.
Bei der Bewertung von Nebenwirkungen werden folgende Häufigkeitsangaben zugrunde gelegt:
Sehr häufig: mehr als 1 von 10 Behandelten
Häufig: weniger als 1 von 10, aber mehr als 1 von 100 Behandelten
Gelegentlich: weniger als 1 von 100, aber mehr als 1 von 1000 Behandelten
Selten: weniger als 1 von 1.000, aber mehr als 1 von 10.000 Behandelten
Sehr selten: weniger als 1 von 10.000 Behandelten, einschließlich Einzelfälle
4.1 Nebenwirkungen
Blut- und Lymphsystem
Gelegentlich: Blutarmut durch vermehrten Zerfall roter Blutkörperchen(hämölytische Anämie), Blutarmut durch Blutbildungsstörung im Knochenmark (aplastische Anämie).
Selten: Verminderung der Anzahl bestimmter Blutzellen (Neutropenie, Thrombozytopenie, Panzytopenie) bis zu einer hochgradigen Verminderung bestimmter weißer Blutkörperchen mit Infektneigung und schweren Allgemeinsymptomen (Agranulozytose), Abnahme bestimmter Laborwerte (Hämoglobin und Hämatokrit), herabgesetzte Funktion des Knochenmarks (Knochenmarksdepression), Lymphknotenschwellung, Autoimmunkrank-heiten.
Stoffwechsel
Gelegentlich: Zu niedrige Blutzuckerwerte (Hypoglykämie).
Augen
Sehr häufig: Verschwommensehen.
Nervensystem
Häufig: Kopfschmerzen, Depressionen.
Gelegentlich: Verwirrtheitszustände, Schläfrigkeit, Schlaflosigkeit, Nervosität, Miss-empfindungen (z.B. Kribbeln, pelziges Gefühl), Schwindel (Vertigo). Selten: Verändertes Träumen, Schlafstörungen.
231
Herz-Kreislauf-System
Sehr häufig: Schwindel. Häufig: Übermäßige Blutdrucksenkung einschließlich übermäßiger Blutdruckabfall bei Lagewechsel vom Liegen zum Stehen (orthostatische Hypotonie), kurzzeitiger Bewusstseinsverlust (Synkope), Herzinfarkt oder Schlaganfall, vermutlich infolge übermäßigen Blutruckabfalls bei gefährdeten Patienten (Patienten mit Durchblutungsstörungen im Bereich des Herzens und/oder des Gehirns), Schmerzen im Brustkorb, Herzrhythmusstörungen, Herzengegefühl (Angina pectoris), beschleunigter Herzschlag (Tachykardie). Gelegentlich: Übermäßiger Blutdruckabfall bei Lagewechsel vom Liegen zum Stehen (orthostatische Hypotonie), Herzklopfen. Selten: Durch Gefäßkrämpfe bedingte Durchblutungsstörungen an Händen und Füßen (Raynaud-Phänomen).
Atemwege
Sehr häufig: Husten. Häufig: Atemnot (Dyspnoe). Gelegentlich: Verstärkte Schleimabsonderung aus der Nase (Rhinorrhö), Halsschmerzen und Heiserkeit, krampfartige Verengung der Bronchien (Bronchospasmus), Asthma. Selten: Auffälligkeiten im Lungengewebe (pulmonale Infiltrate), Schnupfen, allergische Entzündungen der Lunge (allergische Alveolitis /eosinophile Pneumonie).
Magen-Darm-Trakt
Sehr häufig: Übelkeit. Häufig: Durchfall, Bauchschmerzen, Geschmacksveränderungen. Gelegentlich: Darmverschluss (Ileus), Entzündung der Bauchspeicheldrüse, Erbrechen, Verdauungsstörungen, Verstopfung, Appetitlosigkeit, Magenreizung, Mundtrockenheit, Magengeschwür (peptisches Ulkus). Selten: Entzündungen der Mundschleimhaut mit Geschwürbildung (Stomatitis/aphthöse Ulzerationen), Entzündungen der Zungenschleimhaut (Glossitis). Sehr selten: Gewebeschwellung des Darms (intestinales angioneurotisches Ödem).
Leber und Galle
Selten: Leberversagen, Leberentzündung (Hepatitis - hepatozellulär oder cholestatisch, ein-schließlich hepatische Nekrose), Gelbsucht.
Haut und Unterhautgewebe
Häufig: Ausschlag, Überempfindlichkeit/Gewebeschwellung (angioneurotisches Ödem): angioneurotische Ödeme mit Beteiligung von Gesicht, Gliedmaßen, Lippen, Zunge, Stimm-apparat des Kehlkopfes (Glottis) und/oder Kehlkopf wurden beobachtet. Gelegentlich: Vermehrtes Schwitzen, Juckreiz, Nesselsucht, Haarausfall. Selten: Schwerwiegende Hautreaktionen (Erythema multiforme, Stevens-Johnson-Syndrom, exfoliative Dermatitis, toxische epidermale Nekrolyse, Pemphigus, Erythroderma).
232
Ein Symptomenkomplex wurde beschrieben, der mit einigen oder allen der folgenden Nebenwirkungen einhergehen kann: Fieber, Entzündung seröser Häute (Serositis), Gefäßent-zündung (Vaskulitis), Muskel- und Gelenkschmerzen/Muskel- und Gelenkentzündungen (Myalgien/Myositis, Arthralgien/ Arthritis) und bestimmten Laborwertveränderungen (positive ANA-Titer, erhöhte Blutkörperchensenkungsgeschwindigkeit , Eosinophilie und Leukozytose). Hautausschlag, Lichtempfindlichkeit oder andere Reaktionen der Haut können auftreten.
Nieren und ableitende Harnwege
Gelegentlich: Nierenfunktionsstörungen, Nierenversagen, vermehrte Eiweißausscheidung im Urin (Proteinurie). Selten: Verminderte Harnausscheidung (Oligurie).
Fortpflanzungsorgane und Brust
Gelegentlich: Impotenz. Selten: Vergrößerung der Brust bei Männern (Gynäkomastie).
Allgemein
Sehr häufig: Schwächegefühl. Häufig: Müdigkeit. Gelegentlich: Muskelkrämpfe, Gesichtsrötung (Flush), Ohrgeräusche (Tinnitus), Unwohlsein, Fieber.
Laborwerte
Häufig: Anstieg der Kaliumwerte im Blut, Anstieg der Kreatininwerte im Blut. Gelegentlich: Anstieg des Harnstoffs im Blut, Abnahme der Natriumwerte im Blut. Selten: Erhöhte Leberwerte (Leberenzyme, Serum-Bilirubin).
4.2. Gegenmaßnahmen
Falls Sie den Verdacht haben, dass sich bei Ihnen eine schwerwiegende Hautreaktion
entwickelt, müssen Sie sofort Ihren Arzt aufsuchen und gegebenenfalls die Behandlung mit /.../
abgebrechen.
Eine Gewebeschwellung (angioneurotisches Ödem) mit Beteiligung von Kehlkopf, Stimmapparat
des Kehlkopfes und/oder Zunge muss von Ihrem Arzt sofort mit Notfallmedikamenten behandelt
werden.
Wenn bei Ihnen eine Gelbsucht auftritt oder die Leberenzymwerte bei Ihnen deutlich ansteigen,
müssen Sie die Behandlung abbrechen, und Ihr Arzt wird Sie überwachen.
Beim Auftreten von Fieber, Lymphknotenschwellungen und/oder Halsentzündung benachrichtigen
Sie bitte umgehend Ihren Arzt, damit er das weiße Blutbild untersuchen kann.
Sollten Sie die oben genannten Nebenwirkungen bei sich beobachten, benachrichtigen Sie Ihren Arzt. Er wird über den Schweregrad und gegebenenfalls über erforderliche weitere Maßnahmen entscheiden.
233
4.3 Informieren Sie Ihren Arzt oder Apotheker, wenn Sie Nebenwirkungen bermerken, die
nicht in dieser Packungsbeilage aufgeführt sind.
PC5 5. WIE IST /.../ AUFZUBEWAHREN?
Arzneimittel für Kinder unzugänglich aufbewahren.
PZ Sie dürfen das Arzneimittel nach dem auf dem [Packmittel] angegebenen Verfallsdatum nicht mehr verwenden.
P1 <Hinweis auf Haltbarkeit nach Anbruch oder Zubereitung>
P2 Tabletten vor Licht schützen!
P9 <Sie dürfen /.../ nicht verwenden, wenn Sie folgendes bemerken: {Beschreibung der sichtbaren Anzeichen von Nichtverwendbarkeit}>
P6 Stand der Information:
PC6 6. WEITERE ANGABEN
234
Appendix 2: German BfArM text package leaflet with model template
235
236
Appendix 3: German BfArM text package leaflet with QRD template 7.3.1
237
238
Appendix 4: German BfArM text package leaflet with QRD template 8
239
240
Appendix 5: German short text package leaflet with model template
241
242
Appendix 6: German short text package leaflet with QRD template 7.3.1
243
244
Appendix 7: German short text package leaflet with QRD template 8
245
246
Appendix 8: English short text package leaflet with model template
247
248
Appendix 9: English short text package leaflet with QRD template 7.3.1
249
250
Appendix 10: English short text package leaflet with QRD template 8
251
252
Appendix 11: Questionnaire in English with possible correct answers used in the third round of the
readability test
Anna Wolf Am Boden 18 96215 Lichtenfels / Eichig Germany
Improved medication leaflets – a research project Lichtenfels, December 2012
Dear Sir/Madam,
Thank you very much for so generously giving of your time to participate in our project with the aim of improving medication leaflets. You will be pleased to know that we are now in the home straight, and the third and final; leaflet in the series is enclosed for your consideration and completion of the questionnaire.
Information leaflets from medicine packages are frequently criticised. The extended length of the text, too small a print size, scientific terms and long, complicated sentences are the most common complaints. Our goal is to improve package leaflets to the needs of the user.
This survey is anonymous.. Your task, as before, will be to complete a questionnaire to evaluate the package leaflet - how easy it is to understand and is it patient friendly? The results will assist you and many others to understand package leaflets with less difficulty in the future and thus achieve better health by using medication correctly. We do not wish to test your general knowledge or your memory, but only the enclosed package leaflet. Please answer all questions in the questionnaire using the package leaflet provided and return it within 2 weeks. Answering the general questions below is beneficial for our evaluation. We would like to thank you for your support. Yours Sincerely Anna Wolf
___________________________________________________________________________
General questions about yourself: - please fill in all boxes -
Date of completion of questionnaire:…………………Postcode of
residence:……………………………...
Age:…………………. Gender: …………………. First language: ……………………………………….
- Level of education completed to date:
Primary School GCSE/GCE
A-level Technical college
University (number of years attended......) Other
- Last practised occupation
………………………………………………………………………………………
- How many different pharmaceuticals do you take on average every day?
none, 1, 2, 3 to 4, 5 to 7, 8 to 10, more than 10
- Please list the pharmaceuticals you take regularly.
………………………………………………………………………………………………………………
Each day, how long do you spend, on average, reading books, newspapers, magazines, etc?
……………… (hours)
In an average week, how many hours do you hear, read or see reports on medicines and
medical treatments?………(hours)
253
Part 1: First read the entire package information leaflet and then answer the following questions
referring to the leaflet as necessary. These questions are related to the medicine described in
the leaflet. Tick the right-hand column if you are unable to find an answer in the leaflet.
Please note the time you need from start.................... to finish.................... to answer the
following 26 questions.
Questions Your answer
Please tick here
if no answer
was found.
1. How should Enal be stored in relation to
children?
Inaccessible to children
2. What should you do, if you have taken too
much Enal?
Contact a doctor
3. Name the active substance in Enal? Enalapril
4. How frequent is the side effect ‘hair loss’? Uncommon or affects 1 to 10
people of 1000
5 What is the starting dose of Enal to treat
high blood pressure in adults?
1/4 tablet once daily (comprised
text) or once daily 5 mg (BfArM)
6. Should women who think that they might
be pregnant use this medicine?
No
7. Should you give Enal to other people to
use with a similar illness?
No
8. Name one side effect which requires that
you immediately contact your doctor.
Hypersensitivity reactions
9. Can this tablet be divided? Yes
10. What should you do if you have just had a
kidney transplant and you need Enal?
Consult your doctor
11. Name one medicine that is used to treat
heart rhythm disorders which can
influence Enal.
procainamide
12. What is Enal used to treat? High blood pressure
Heart failure
13 Can you take this medicine if you are
allergic to lactose?
No
14. What should you do if you want to stop
taking this medicine?
Consult a doctor
15. What should you do with regard to
drinking alcohol when taking this
medicine?
Not drink it
254
16. How many people are affected by a side
effect if it is ‘rare’?
Please, write you answer in numbers, for
example <...> of <.....> people
Either from table or other verbal
descriptor
17. Write down one reason why your ability to
drive may be reduced due to taking Enal.
Reaction time is affected
+ side effects in Sect. 4
18. What is Enal used for treating in children? high blood pressure
19. What should you do if you forget to take a
dose of this medicine?
Not take the double dose
20. What should you do if you need a dental
operation while taking Enal?
Tell the dentist
21. Is this medicine available with or without
prescription by a doctor?
with
22. What should you do if you already take
medicines to reduce blood sugar levels
and also need Enal?
Consult a doctor
23. In which of the side effect frequency
groups does the following frequency:
‘affects 5 in 100 people’ belong?
common
24. What should you do if you notice the side
effect runny nose?
Tell your doctor
25. Under what circumstances may breast-
feeding women take Enal?
‘Older nurslings’ (BfArM text)
and ‘contraindicated’ comprised
text
26 How long should Enal be used? decided by the doctor
Please write the time at the top of the table!
Please go to part 2 overleaf.
255
Part 2: Below are different statements relating to the attached package leaflet. Please tick the
boxes according to your opinion. – Only one tick per statement please! -
Statement
Your opinion
Yes mostly
yes Other
mostly
no
not at
all
1. The information requested in part 1 was easy to
find.
2. The first impression of this package leaflet
motivated me to read further.
3. The content of this package leaflet was difficult
to understand.
4. This package leaflet provided all the instructions
I needed to use this medicine.
5. Complicated sentences were used in this
package leaflet.
6. Each subheading clarifies the information
contained in the following section.
7. I feel well informed from the information
contained within this package leaflet.
8. This package leaflet contained too much
information for me.
9. The text is easy to read.
10. The content of this package leaflet raises my
concerns about using this medicine.
11. This package leaflet contains difficult words.
12. I found all information which is of importance to
me at the beginning of this package leaflet.
13. Some information about the medicine is missing
from the package leaflet.
14. Does the benefit of taking this medicine outweigh
the potential risks?
15. Would you like all package leaflets to be similar
to this one?
Part 3: Please write down:
What do you like most about this package leaflet?
.........................................................................................................................................................
What do you dislike most about this package leaflet?
.........................................................................................................................................................
Which additional information do you think should be included in this package leaflet?
........................................................................................................................................................
Which information should be deleted in your opinion in the package leaflet? (Please mark in the package leaflet) Thank you for your support!
256
Appendix 12: Questionnaire in German used in the third round of the readability test – The date
was changed at the start of the questionnaire during each round of the readability test
Anna Wolf
Am Boden 18
96215 Lichtenfels / Eichig
Deutschland
Lichtenfels, Dezember 2012
Sehr geehrte Damen und Herren,
vielen herzlichen Dank, dass Sie so großzügig Ihre Zeit für die Teilnahme an unserem Projekt
zur Verbesserung der Packungsbeilagen geopfert haben. Es wird Sie freuen zu hören, dass wir
nun mit der dritten und letzten Beilage auf der Zielgeraden sind. Die beiliegende Seiten
übergeben wir Ihnen nun zur Durchsicht und Vollendung des Fragebogens.
Packungsbeilagen von Arzneimitteln werden häufig kritisiert. Dabei gehören lange Texte, zu
kleine Schriftgrößen, Fremdwörter und lange, komplizierte Sätze zu den häufigsten Problemen.
Unser Ziel ist es, Packungsbeilagen den Wünschen und Bedürfnissen der Verbraucher
anzupassen.
Diese Befragung ist anonym. Ihre Aufgabe besteht darin wie bisher, die Packungsbeilagen
dahingehend zu bewerten, wie verständlich und patientenfreundlich sie sind. Die Ergebnisse
sollen Ihnen und vielen anderen Menschen in der Zukunft den Umgang mit Packungsbeilagen
erleichtern. In dieser Studie möchten wir nicht Ihr Allgemeinwissen oder Denkvermögen testen,
sondern die Ihnen ausgehändigte Packungsbeilage. Bitte beantworten Sie deshalb jede Frage
des Fragebogens unter Gebrauch der ausgehändigten Packungsbeilage innerhalb von zwei
Wochen.
Für Ihre Unterstützung bedanken wir uns.
Mit freundlichen Grüßen
Anna Wolf
___________________________________________________________________________
Allgemeine Angaben zu Ihrer Person: - Bitte füllen sie alle Felder aus! -
Datum, an dem der Fragebogen ausgefüllt wurde:.......... Postleitzahl des Wohnortes: ................
Alter: ...........................Geschlecht: ......................Muttersprache: ...................................................
- abgeschlossene Ausbildung:
8. Klasse 10. Klasse
Abitur Fachhochschule
Hochschule/Universität (Anzahl Hochschul/Unijahre.....) Andere
-Zuletzt ausgeübter Beruf ......................................................................................................
- Wie viele Medikamente wenden Sie durchschnittlich pro Tag an?
keine, 1, 2, 3 bis 4, 5 bis 7, 8 bis 10, mehr als 10
- Bitte geben Sie an, welche Medikamente Sie regelmäßig anwenden!
......................................................................................................................................................
Wie lange lesen Sie durchschnittlich pro Tag (Bücher, Zeitungen, Zeitschriften usw.)?..(Stunden)
Wie häufig hören, sehen oder lesen Sie medizinische Berichte pro Woche?................. (Stunden)
257
Teil 1: Lesen Sie bitte zuerst die gesamte Packungsbeilage und beantworten Sie danach die nachfolgenden Fragen. Diese Fragen beziehen sich auf den Inhalt der Packungsbeilage. Kreuzen Sie bitte in der rechten Spalte an, falls Sie keine Antwort in der Packungsbeilage finden konnten. Geben Sie unbedingt die Uhrzeit von Beginn .................... und Ende .................... des Beantwortens der folgenden 26 Fragen des Fragebogens an.
Zu beantwortende Frage Ihre Antwort
Falls keine
Antwort gefunden
wurde, bitte hier
ein Kreuz!
1. Wie sollte Enal in Bezug zu Kindern
aufbewahrt werden?
2. Was sollten Sie tun, wenn Sie zu viel Enal
eingenommen haben?
3. Nennen Sie den Wirkstoff von Enal?
4. Wie häufig tritt die Nebenwirkung
„Haarausfall’ auf?
5 Was ist die Anfangsdosis von Enal zur
Behandlung von Bluthochdruck bei
Erwachsenen?
6. Sollten Frauen, die möglicherweise
schwanger sind, dieses Arzneimittel
einnehmen?
7. Sollten Sie Enal an andere Personen mit
ähnlichen Krankheiten zum Gebrauch
weitergeben?
8. Nennen Sie eine Nebenwirkung, die einen
sofortigen Kontakt des Arztes erfordert.
9. Kann diese Tablette geteilt werden?
10. Was sollten Sie tun, wenn Sie kürzlich
eine Nierentransplantation hatten und
Enal einnehmen sollen?
11. Nennen Sie ein Arzneimittel, das zur
Behandlung von Herzrhythmusstörungen
verwendet wird und die Wirkung von Enal
beeinflussen kann.
12. Wofür wird Enal angewendet?
13 Dürfen Sie dieses Arzneimittel einnehmen,
wenn Sie auf Laktose allergisch sind?
258
14. Was sollten Sie tun, wenn Sie die
Einnahme dieses Arzneimittel beenden
möchten?
15. Wie sollten Sie sich hinsichtlich des
Trinkens von Alkohol verhalten, wenn Sie
dieses Arzneimittel einnehmen?
16. Wie viele Personen sind von einer
Nebenwirkung betroffen, wenn sie ‘selten’
ist?
Bitte in Zahlen angeben, wie: <……> von <…….> Personen
17. Nennen Sie einen Grund, weshalb Ihre
Fahrtauglichkeit durch Einnahme von Enal
verringert sein kann.
18. Gegen welche Krankheit wird Enal bei
Kindern verwendet?
19. Was ist zu tun, wenn Sie die Anwendung
dieses Medikamentes einmal vergessen
haben?
20. Was sollten Sie tun, wenn Sie eine
Zahnoperation benötigen und Enal
einnehmen?
21. Ist das Medikament mit oder ohne
ärztliche Verschreibung erhältlich?
22. Was sollten Sie tun, wenn Sie bereits
Arzneimittel zur Blutzuckersenkung
einnehmen und Enal benötigen?
23. Zu welcher Nebenwirkungsgruppe gehört
folgende Häufigkeit: „betrifft 5 von 100
Personen’?
24. Was sollten Sie tun, wenn Sie die
Nebenwirkung Schnupfen feststellen?
25. Wann dürfen stillende Frauen Enal
einnehmen?
26 Wie lange sollte Enal angewendet
werden?
Bitte Uhrzeit oberhalb der Tabelle eintragen!
Bitte gehen Sie nun zum Teil 2 auf der Rückseite!
259
Teil 2: Hier sind verschiedene Aussagen zu der Ihnen vorliegenden Packungsbeilage genannt.
Bewerten Sie jede entsprechend Ihrer persönlichen Meinung. - Bitte immer nur eine Aussage ankreuzen! -
Zu bewertende Aussage
Ihre Meinung
ja eher
ja
trifft
weder
noch zu
eher
nein
nein
1. Die im Teil 1 erfragten Informationen konnte ich
leicht im Text finden.
2. Mein erster Eindruck von der Packungsbeilage
motiviert mich, sie zu lesen.
3. Der Text dieser Packungsbeilage ist schwer
verständlich.
4. Diese Packungsbeilage erklärt mir ausreichend
alle wichtigen Fragen zu diesem Arzneimittel.
5. In dieser Packungsbeilage wurden komplizierte
Sätze verwendet.
6. Jede Zwischenüberschrift verdeutlicht, welche
Informationen der folgende Abschnitt enthält.
7. Ich fühle mich durch diese Packungsbeilage
über das Arzneimittel gut informiert.
8. Für mich sind zu viele Informationen in dieser
Packungsbeilage enthalten.
9. Der Text ist für mich gut lesbar.
10. Der Inhalt dieser Packungsbeilage beängstigt
mich, das Arzneimittel anzuwenden.
11. In dieser Packungsbeilage sind Fremdwörter
enthalten.
12. Informationen, die mich sehr interessieren, sind
zu Beginn in dieser Packungsbeilage enthalten.
13. In dieser Packungsbeilage fehlen mir
Informationen zu diesem Arzneimittel.
14. Überwiegt der Nutzen dieses Arzneimittels die
möglichen Gefahren?
15. Wünschen Sie sich, dass alle Packungsbeilagen
so sind wie diese?
Teil 3: Notieren Sie bitte:
Was finden Sie an dieser Packungsbeilage besonders gut? ...........................................................................................................................................................
Was finden Sie an dieser Packungsbeilage besonders schlecht?
.........................................................................................................................................................
Welche Informationen sollten Ihrer Meinung nach zusätzlich in diese Packungsbeilage aufgenommen werden?
.........................................................................................................................................................
Welche Informationen sollten Ihrer Meinung nach nicht in der Packungsbeilage enthalten sein? (Bitte markieren Sie diese in der Packungsbeilage) Vielen Dank für Ihre Unterstützung!
260
Appendix 13: Results of the Wilcoxon test to identify significant differences between package leaflet versions for number of correct answers,
wrong answers and not found answers for the 26 content questions of the readability test
Compared package leaflets
(EN = English, DE = German)
Significance between leaflet versions
Correct
answers
Wrong answers Not found
answers
EN-Model-template-short text EN-QRD- template-7.3.1-short text p < 0.001 p < 0.001 n.s
EN-Model- template-short text EN-QRD- template-8-short text p < 0.001 p < 0.001 n.s
EN-QRD- template-7.3.1-short text EN-QRD- template-8-short text p < 0.001 p < 0.001 n.s
DE-Model- template-short text DE-QRD- template-7.3.1-short text p < 0.001 p < 0.001 p = 0.006
DE-Model- template-short text DE-QRD- template-8-short text p = 0.026 p < 0.001 n.s
DE-QRD- template-7.3.1-short text DE-QRD- template-8-short text p = 0.002 p < 0.001 n.s
DE-Model- template-BfArM text DE-QRD- template-7.3.1-BfArM text p = 0.001 p < 0.001 p < 0.001
DE-Model- template-BfArM text DE-QRD- template-8-BfArM text n.s p < 0.001 p < 0.001
DE-QRD- template-7.3.1-BfArM text DE-QRD- template-8-BfArM text p < 0.001 p = 0.001 n.s
261
Appendix 14: Results of the McNemar test to identify significant differences in the number of correct answers between short versions of the
package leaflets in England (Only the results for the 5 of the 26 content questions which showed significant differences between different versions of
the package leaflet are shown)
Compared package leaflets
(EN = English)
Question
What should you do
if you have just had
a kidney transplant
and you need Enal?
Can you take
this medicine if
you are allergic
to lactose?
What should you do if
you need a dental
operation while taking
Enal?
In which of the side
effect frequency
groups does the
following frequency:
‘affects 5 in 100
people’ belong?
What should you
do if you notice
the side effect
runny nose?
EN-Model-
template-short
text
EN-QRD-
template-7.3.1-
short text
p < 0.001 n.s p < 0.001 p = 0.001 p < 0.001
EN-Model-
template-short
text
EN-QRD-
template-8-short
text
n.s p = 0.015 p = 0.002 p < 0.001 p = 0.012
EN-QRD-
template-
7.3.1-short
text
EN-QRD-
template-8-short
text p < 0.001 n.s p < 0.001 p = 0.002 p < 0.001
262
Appendix 15: Results of the McNemar test to identify significant differences in the number of correct answers between short versions of the
package leaflets in Germany (Only the results for the 3 of the 26 content questions which showed significant differences between different versions
of the package leaflet are shown)
Compared package leaflets
(DE = German)
Question
What should you do if
you have had a kidney
transplant and you need
Enal?
What should you do if
you need a dental
operation while taking
Enal?
In which of the side effect
frequency groups does the
following frequency ‘affects
5 in 100 people’ belong?
DE-Model-
template-short
text
DE-QRD-template-
7.3.1-short text p < 0.001 p < 0.001 p = 0.031
DE-Model-
template-short
text
DE-QRD-template-
8-short text n.s n.s p < 0.001
DE-QRD-
template-7.3.1-
short text
DE-QRD-template-
8-short text p < 0.001 p < 0.001 p < 0.001
263
Appendix 16: Results of the McNemar test to identify significant differences in the number of correct answers between long versions of the
package leaflets in Germany (Only the results for the 7 of the 26 content questions which showed significant differences between different versions
of the package leaflet are shown)
Compared package leaflets
(DE = German)
Question
How
frequent is
the side
effect
hairloss?
Can this
tablet be
divided?
What should you
do if you have
had a kidney
transplant and
you need Enal?
What should
you do if you
want to stop
taking this
medicine?
In which of the
side effect
frequency groups
does the following
frequency ‘affects
5 in 100 people’
belong?
What
should you
do if you
notice the
side effect
runny nose?
How long
should Enal
be used?
DE-Model-
template-
BfArM text
DE-QRD-
template 7.3.1-
BfArM text
n.s n.s p < 0.001 n.s p = 0.018 n.s p = 0.002
DE-Model-
template-
BfArM text
DE-QRD-
template-8-
BfArM text
p = 0.031 p = 0.001 n.s n.s p < 0.001 p = 0.009 n.s
DE-QRD-
template-
7.3.1-BfArM
text
DE-QRD-
template-8-
BfArM text p = 0.006 p = 0.024 p < 0.001 p = 0.035 p < 0.001 n.s n.s
264
Appendix 17: Results of the McNemar test to identify significant differences in the number of wrong answers between short versions of the
package leaflets in England (Only the results for the 5 of the 26 content questions which showed significant differences between different versions of
the package leaflet are shown)
Compared package leaflets
(EN = English)
Question
What should you do
if you have just had a
kidney transplant
and you need Enal?
Can you take this
medicine if you are
allergic to lactose?
What should
you do if you
need a dental
operation while
taking Enal?
In which of the side
effect frequency
groups does the
following
frequency: ‘affects
5 in 100 people’
belong?
What should you do
if you notice the side
effect runny nose?
EN-Model-
template-short text
EN-QRD-
template-7.3.1-
short text
p < 0.001 p = 0.004 p < 0.001 p = 0.002 p < 0.001
EN-Model-
template-short text
EN-QRD-
template-8-short
text
n.s p < 0.001 n.s p < 0.001 n.s
EN-QRD-template-
7.3.1-short text
EN-QRD-
template-8-short
text
p < 0.001 n.s p < 0.001 n.s p < 0.001
265
Appendix 18: Results of the McNemar test to identify significant differences in the number of wrong answers between short versions of the
package leaflets in Germany (Only the results for the 5 of the 26 content questions which showed significant differences between different versions
of the package leaflet are shown)
Compared Package leaflets
(DE = German)
Question
What should you
do if you have
just had a kidney
transplant and
you need Enal?
Can you take this
medicine if you are
allergic to lactose?
What should you do
if you need a dental
operation while
taking Enal?
In which of the
side effect
frequency groups
does the following
frequency: ‘affects
5 in 100 people’
belong?
What should you
do if you notice
the side effect
runny nose?
DE-Model-
template-short text
DE-QRD-template
7.3.1-short text p < 0.001 p = 0.004 p < 0.001 p = 0.006 n.s
DE-Model-
template-short text
DE-QRD-template-
8-short text n.s p = 0.035 n.s p < 0.001 n.s
DE-QRD-template-
7.3.1-short text
DE-QRD-template-
8-short text p < 0.001 n.s p < 0.001 p = 0.004 p = 0.008
266
Appendix 19: Results of the McNemar test to identify significant differences in the number of wrong answers between long versions of the
package leaflets in Germany (Only the results for the 4 of the 26 content questions which showed significant differences between different versions
of the package leaflet are shown)
Compared package leaflets
(DE = German)
Question
How frequent is the
side effect ‘hair loss’?
What should you do if
you have had a kidney
transplant and you need
Enal?
Can you take this
medicine if you are
allergic to lactose?
In which of the side
effect frequency
groups does the
following frequency:
‘affects 5 in 100
people’ belong?
DE-Model-template-
BfArM text
DE-QRD-template 7.3.1-
BfArM text p < 0.001 p < 0.001 n.s p = 0.007
DE-Model-template-
BfArM text
DE-QRD-template-8-
BfArM text n.s p = 0.031 p < 0.001 p < 0.001
DE-QRD-template-7.3.1-
BfArM text
DE-QRD-template-8-
BfArM text p < 0.001 p < 0.001 n.s p = 0.013
267
Appendix 20: Results of the McNemar test to identify significant differences in the number of not found answers between short versions of the
package leaflets in England (Only the results for the 5 of the 26 content questions which showed significant differences between different versions of
the package leaflet are shown)
Compared package leaflets
(EN = English)
Question
What should you do
if you have just had a
kidney transplant
and you need Enal?
Can you take
this medicine if
you are allergic
to lactose?
What should you
do if you need a
dental operation
while taking
Enal?
In which of the side
effect frequency
groups does the
following frequency:
‘affects 5 in 100
people’ belong?
What should you do if
you notice the side effect
runny nose?
EN-Model-
template-short
text
EN-QRD-
template-7.3.1-
short text
p = 0.021 p < 0.001 n.s n.s n.s
EN-Model-
template-short
text
EN-QRD-
template-8-short
text
p = 0.021 p < 0.001 p = 0.002 p = 0.013 p = 0.021
EN-QRD-
template-7.3.1-
short text
EN-QRD-
template-8-short
text
n.s n.s n.s p = 0.049 p < 0.001
268
Appendix 21: Results of the McNemar test to identify significant differences in the number of not found answers between short versions of the
package leaflets in Germany (Only the results for the 4 of the 26 content questions which showed significant differences between different versions
of the package leaflet are shown)
Compared package leaflets
(DE = German)
Question
Can you take this
medicine if you are
allergic to lactose?
What should you do
if you need a dental
operation while
taking Enal?
Is this medicine
available with or
without
prescription by a
doctor?
In which of the side
effect frequency
groups does the
following frequency:
‘affects 5 in 100
people’ belong?
DE-Model-template-short
text
DE-QRD-template 7.3.1-
short text p < 0.001 p = 0.016 p = 0.003 n.s
DE-Model-template-short
text
DE-QRD-template-8-
short text p < 0.001 n.s p = 0.035 p = 0.001
DE-QRD-template-7.3.1-
short text
DE-QRD-template-8-
short text n.s n.s n.s p < 0.001
269
Appendix 22: Results of the McNemar test to identify significant differences in the number of not found answers between long versions of the
package leaflets in Germany (Only the results for the 26 content questions which showed significant differences between different versions of the
package leaflet are shown)
Compared package leaflets
(DE = German)
Question
How frequent is the
side effect ‘hair loss’?
What is the starting
dose of Enal to treat
high blood pressure
in adults?
Name one side
effect which
requires that you
immediately contact
your doctor.
Can this tablet
be divided?
What should you do
if you have just had a
kidney transplant
and you need Enal?
DE-Model-
template-BfArM
text
DE-QRD-
template 7.3.1-
BfArM text
p = 0.021 p = 0.022 p = 0.021 p = 0.029 n.s
DE-Model-
template-BfArM
text
DE-QRD-
template-8-
BfArM text
p = 0.021 n.s p = 0.012 p < 0.001 p = 0.035
DE-QRD-
template-7.3.1-
BfArM text
DE-QRD-
template-8-
BfArM text
n.s p < 0.001 n.s n.s p = 0.035
270
Appendix 23: Results of the McNemar test to identify significant differences in the number of not found answers between long versions of the
package leaflets in Germany (Only the results for the 26 content questions which showed significant differences between different versions of the
package leaflet are shown)
Compared package leaflets
(DE = German)
Question
Can you take this
medicine if you are
allergic to lactose?
What should you
do with regard
to drinking
alcohol when
taking this
medicine?
In which of the side
effect frequency groups
does the following
frequency: ‘affects 5 in
100 people’ belong?
What should you
do if you notice
the side effect
runny nose?
How long should
Enal be used?
DE-Model-
template-BfArM
text
DE-QRD-
template 7.3.1-
BfArM text
p < 0.001 n.s n.s p = 0.005 p = 0.007
DE-Model-
template-BfArM
text
DE-QRD-
template-8-
BfArM text
p < 0.001 n.s p < 0.001 p = 0.004 n.s
DE-QRD-template-
7.3.1-BfArM text
DE-QRD-
tempalte-8-
BfArM text
n.s p = 0.008 p < 0.001 n.s n.s
271
Appendix 24: Results of the Pearson’s chi-square test to identify significant differences in the time taken to answer the 26 content questions
according to age group for the long versions of the package leaflet in Germany
Compared age group (years) Significance
≤ 19 20 – ≤ 39 p < 0.001
≤ 19 40 – ≤ 59 p < 0.001
≤ 19 ≥ 60 p < 0.001
20 – ≤ 39 40 – ≤ 59 n.s
20 – ≤ 39 ≥ 60 p < 0.001
40 – ≤ 59 ≥ 60 p < 0.001
272
Appendix 25: Results of the Pearson’s chi-square test to identify significant differences in the time taken to answer the 26 content questions
according to number of medicines taken per day for the long versions of the package leaflet in Germany
Compared number of medicines
taken per day Significance
0 1 n.s
0 2 p < 0.001
0 ≥ 3 p < 0.001
1 2 p = 0.016
1 ≥ 3 p < 0.001
2 ≥ 3 n.s
273
Curriculum vitae
Name: Anna Wolf (nee Smith)
Date of birth: 23.11.1973
Place of birth: Cambridge, United Kingdom
Nationality: British
Marital status: Married, two children
School Education
1978 - 1985: Mayfield Primary School, Cambridge
1985 - 1990: Chesterton Community College, Cambridge
1990 - 1992: Long Road Sixth Form College, Cambridge (A - Levels)
University Education
1992 - 1996: London University, Imperial College of Science, Technology and Medicine.
Two terms at University of Bayreuth
Degree in Biology with first class honours
1996 - 1998: European Molecular Biology Laboratory, Heidelberg.
Master of Philosophy
Awards: Imperial College Governors Prize in Biology 1996
Memberships: Associate of the Royal College of Science
Employment History
1998 - 2000: University of Bayreuth, Assistant in the Department of Genetics
2000 - 2005: University of Bayreuth, Assistant in the Department of Microbiology
2006 - 2010: Dr. R. Pfleger Chemische Fabrik GmbH, Bamberg, Consultant for Drug
Safety/Medical Information
Since 2010: Dr. R. Pfleger Chemische Fabrik GmbH, Bamberg, Project Manager for Medical
Information
274
Author’s declaration
I, Anna Wolf, born Smith, hereby confirm that according to Paragraph 8 of the doctoral degree
regulations, that the presented work was completed independently and that no other source materials or
aids were used other than those stipulated.
Eichig, the _________________________ (Anna Wolf)
275
Acknowledgements
Firstly I would like to thank Professor Dr. Harald Schweim for providing the possibility to carry out this
research and his support and advice during the project. Thank you to the other members of the Drug
Regulatory Affairs group for the interesting discussions during our ‘Doktorandentage’.
A special thanks to Dr. Jörg Fuchs, who I would like to express my sincere gratitude to for his continuous
support, patience, motivation, and enthusiasm throughout all phases of this work.
Thank you to the members of my thesis committee for their time.
Here I would also like to thank everybody in Germany and England who read a package leaflet and
answered a questionnaire which made the readability test in this project possible at all. A special thanks
also to my parents for co-ordinating the part of the readability test in England and to my father for helpful
comments regarding the writing of the thesis.
Finally, I would like to thank my husband, Roland and daughters Grace and Rebecca who were always
there for me.